Degradation of protein kinases by conjugation of protein kinase inhibitors with e3 ligase ligand and methods of use

ABSTRACT

The present application provides bifunctional compounds of Formula (X): 
     
       
         
         
             
             
         
       
     
     or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases. The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.

RELATED APPLICATION

This application claims priority to, and the benefit of, U.S.Application No. 62/425,587, filed on Nov. 22, 2016, the entire contentsof which are incorporated herein by reference.

BACKGROUND

Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulatesproteins and degrades misfolded or abnormal proteins. UPP is central tomultiple cellular processes, and if defective or imbalanced, leads topathogenesis of a variety of diseases. The covalent attachment ofubiquitin to specific protein substrates is achieved through the actionof E3 ubiquitin ligases. These ligases comprise over 500 differentproteins and are categorized into multiple classes defined by thestructural element of their E3 functional activity. For example,cereblon (CRBN) interacts with damaged DNA binding protein 1 and formsan E3 ubiquitin ligase complex with Cullin 4 in which the proteinsrecognized by CRBN are ubiquitinated and degraded by proteasomes.Various immunomodulatory drugs (IMiDs), e.g., thalidomide andlenalidomide, binds to CRBN and modulates CRBN's role in theubiquitination and degradation of protein factors involved inmaintaining regular cellular function.

Bifunctional compounds composed of a target protein-binding moiety andan E3 ubiquitin ligase-binding moiety have been shown to induceproteasome-mediated degradation of selected proteins. These drug-likemolecules offer the possibility of temporal control over proteinexpression, and could be useful as biochemical reagents for thetreatment of diseases.

Protein kinases are a class of enzymes that catalyze the transfer of theterminal phosphate of adenosine triphosphate to amino acid residues suchas tyrosine, serine, and threonine residues on protein substrates.Protein kinases are a large family of proteins which play a criticalrole in the regulation of a wide variety of cellular processes andfunctions. Protein kinases can be broken down into two classes, theprotein tyrosine kinases and the serine-threonine kinases. Proteintyrosine kinases (PTKs) are enzymes which phosphorylate tyrosineresidues in peptides and proteins and which play a key role in theregulation of cell signaling including cell proliferation and celldifferentiation. PTKs include receptor tyrosine kinases (RPTKs) andnon-receptor tyrosine kinases. Enhanced activity of PTKs has beenimplicated in a variety of malignant and nonmalignant proliferativediseases. The serine/threonine kinases, STKs, are the most common of thecytosolic kinases. STKs are enzymes which phosphorylate serine and/orthreonine residues in peptides.

The protein kinase families include, for example, kinases such as Abl,Ack, AIE2, Akt, ALK, ALK2, ALK3, AIM1, ARK2, ARK1, AURA, Aurora-A,Aurora-B, Aurora-C, bcr-abl, Blk, BRAF, Brk, BTAK, Btk, c-fms, c-kit,c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9,CDK10, cRafl, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, Frk, Fes, Fps,FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, fit-1, Fps, Frk, Fyn, Hck,IGF-1R, IRR, INS-R, Jak, KDR/FLK-1, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC,PYK2, ros, Src, STK12, STK13, STK15, STK16, Syk, tie, tie2, TRK, VEGF,Yrk, and Zap70. Abnormal protein kinase activity has been related tonumerous disorders, including psoriasis, cancers, bone disorders,metabolic disorders, inflammatory disorders, and other diseases.

Compounds which inhibit protein kinases via alternative strategies, suchas through degradation of protein kinases, have the potential to be morepotent than known inhibitors of protein kinases and are needed. Thepresent application addresses the need.

SUMMARY

The present application relates to novel bifunctional compounds, whichfunction to recruit targeted proteins to E3 ubiquitin ligase fordegradation, and methods of preparation and uses thereof. Thebifunctional compound is of Formula X:

wherein:

the Targeting Ligand is capable of binding to at least one targetedprotein, such as a protein kinase;

the Linker is a group that covalently binds to the Targeting Ligand andthe Degron; and

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon).

The present application also relates to targeted degradation of proteinsthrough the use of bifunctional compounds, including bifunctionalcompounds that link an E3 ubiquitin ligase-binding moiety to a ligandthat binds the targeted proteins.

The present application also relates to a bifunctional compound ofFormula I, II, III, IV, V, or VI:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

A, B₁, B₂, B₃, B₄, B₅, B₆, B₇, R₁-R₄, R₆-R₈, R₁₂-R₁₄, R₁₇, R₁₈, R₂₁-R₂₄,R₂₇-R₃₀, X₁, X₂, X₃, X₄, Y₁, n1, n2, q1, q2, r1, s2, s3, s4, and s5 areeach as defined herein;

the Linker is a group that covalently binds to

and the degron in Formula (I);

and the degron in Formula (II);

and the degron in Formula (III);

and the degron in Formula (IV);

and the degron in Formula (V); or

and the degron in Formula (VI);

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to at least one targetedproteins, such a protein kinase.

The present application further relates to a Degron of Formula D1 or D2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein Y, Z₃,R₃₇, R₃₈, R₃₉, R₄₀, R₄₁, R₄₂, v, q, and q′ are each as defined herein,and the Degron covalently binds to a Linker via

The present application further relates to a Linker of Formula L1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein p1, p2,p3, W, Q₁, and Z₁, are each as defined herein, the Linker is covalentlybonded to a Degron via the

next to Q₁, and covalently bonded to a Targeting Ligand via the

next to Z₁.

The present application also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of a bifunctional compoundof the application, or an enantiomer, diastereomer, or stereoisomer, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Another aspect of the present application relates to a method ofinhibiting at least one protein kinase. The method comprisesadministering to a subject in need thereof an effective amount of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application. In someembodiments, the bifunctional compound inhibits more than one proteinkinase. In some embodiments, the protein kinase is a protein tyrosinekinase. In other embodiments, the protein kinase is a serine-threoninekinase.

Another aspect of the present application relates to a method ofmodulating (e.g., decreasing) the amount of at least one protein kinase.The method comprises administering to a subject in need thereof atherapeutically effective amount of a bifunctional compound of theapplication, or an enantiomer, diastereomer, or stereoisomer, orpharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the application. In some embodiments, the bifunctionalcompound modulates more than one protein kinase. In some embodiments,the protein kinase is a protein tyrosine kinase. In other embodiments,the protein kinase is a serine-threonine kinase.

Another aspect of the present application relates to a method ofinhibiting a protein tyrosine kinase. The method comprises administeringto a subject in need thereof an effective amount of a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application.

Another aspect of the present application relates to a method ofinhibiting a serine-threonine kinase. The method comprises administeringto a subject in need thereof an effective amount of a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application.

Another aspect of the present application relates to a method ofmodulating a protein tyrosine kinase. The method comprises administeringto a subject in need thereof an effective amount of a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application.

Another aspect of the present application relates to a method ofmodulating a serine-threonine kinase. The method comprises administeringto a subject in need thereof an effective amount of a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application.

Another aspect of the present application relates to a method oftreating or preventing a disease (e.g., a disease in which one or moreprotein kinases (e.g., a protein tyrosine kinase or a serine-threoninekinase) play a role). The method comprises administering to a subject inneed thereof an effective amount of a bifunctional compound of theapplication, or an enantiomer, diastereomer, or stereoisomer, orpharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the application. In one aspect, the disease is proteinkinase mediated disorder. In one aspect, the disease is a proliferativedisease (e.g., a proliferative disease in which one or more proteinkinases play a role). In some embodiments, the method treats or preventsa disease in which a protein tyrosine kinase plays a role. In otherembodiments, the method treats or prevents a disease in which aserine-threonine kinase plays a role.

Another aspect of the present application relates to a method oftreating or preventing cancer in a subject, wherein the cancer cellcomprises an activated protein kinase (or one or more protein kinases)or wherein the subject is identified as being in need of protein kinaseinhibition for the treatment or prevention of cancer. The methodcomprises administering to the subject an effective amount of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable thereof,or a pharmaceutical composition of the application. In some embodiments,the cell comprises more than one activated protein kinase.

In some embodiments, the activated protein kinase is a protein tyrosinekinase. In other embodiments, the activated protein kinase is aserine-threonine kinase.

Another aspect of the present application relates to a method oftreating or preventing cancer in a subject, wherein the cancer cellcomprises an activated protein tyrosine kinase or wherein the subject isidentified as being in need of inhibition of a protein tyrosine kinasefor the treatment or prevention of cancer. The method comprisesadministering to the subject an effective amount of a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable thereof, or apharmaceutical composition of the application.

Another aspect of the present application relates to a method oftreating or preventing cancer in a subject, wherein the cancer cellcomprises an activated serine-threonine kinase or wherein the subject isidentified as being in need of inhibition of a serine-threonine kinasefor the treatment or prevention of cancer. The method comprisesadministering to the subject an effective amount of a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable thereof, or apharmaceutical composition of the application.

Another aspect of the present application relates to a kit comprising abifunctional compound capable of inhibiting protein kinase activity ofat least one protein kinase, selected from a bifunctional compound ofthe application, or an enantiomer, diastereomer, or stereoisomer, orpharmaceutically acceptable salt thereof. In some embodiments, thebifunctional compound inhibits more than one protein kinase. In someembodiments, the bifunctional compound inhibits a protein tyrosinekinase. In other embodiments, the bifunctional compound inhibits aserine-threonine kinase.

Another aspect of the present application relates to a kit comprising abifunctional compound capable of inhibiting protein tyrosine kinaseactivity, selected from a bifunctional compound of the application, oran enantiomer, diastereomer, or stereoisomer, or pharmaceuticallyacceptable salt thereof.

Another aspect of the present application relates to a kit comprising abifunctional compound capable of inhibiting serine-threonine kinaseactivity, selected from a bifunctional compound of the application, oran enantiomer, diastereomer, or stereoisomer, or pharmaceuticallyacceptable salt thereof.

Another aspect of the present application relates to a kit comprising abifunctional compound capable of modulating (e.g., decreasing) theamount of at least one protein kinase, selected from a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof. In someembodiments, the bifunctional compound modulates more than one proteinkinase. In some embodiments, the bifunctional compound modulates aprotein tyrosine kinase. In other embodiments, the bifunctional compoundmodulates a serine-threonine kinase.

Another aspect of the present application relates to a kit comprising abifunctional compound capable of modulating (e.g., decreasing) theamount of a protein tyrosine kinase, selected from a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof.

Another aspect of the present application relates to a kit comprising abifunctional compound capable of modulating (e.g., decreasing) theamount of a serine-threonine kinase, selected from a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for inhibiting at least one protein kinaseor for modulating (e.g., decreasing) the amount of protein kinase. Insome embodiments, the bifunctional compound inhibits more than oneprotein kinase. In some embodiments, the bifunctional compound inhibitsa protein tyrosine kinase. In some embodiments, the bifunctionalcompound inhibits a serine-threonine kinase.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for inhibiting a protein tyrosine kinase orfor modulating (e.g., decreasing) the amount of a protein tyrosinekinase.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for inhibiting a serine-threonine kinase orfor modulating (e.g., decreasing) the amount of a serine-threoninekinase.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for treating or preventing a disease (e.g.,a disease in which one or more protein kinases play a role). In oneaspect, the disease is protein kinase mediated disorder. In one aspect,the disease is a proliferative disease (e.g., a proliferative disease inwhich one or more protein kinases play a role). In another aspect, thedisease is a protein tyrosine kinase mediated disorder. In yet anotheraspect, the disease is a serine-threonine kinase mediated disorder.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for treating or preventing cancer in asubject, wherein the cancer cell comprises at least one activatedprotein kinase or wherein the subject is identified as being in need ofinhibition of at least one protein kinase for the treatment orprevention of cancer.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for treating or preventing cancer in asubject, wherein the cancer cell comprises an activated protein tyrosinekinase or wherein the subject is identified as being in need ofinhibition of a protein tyrosine kinase for the treatment or preventionof cancer.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for treating or preventing cancer in asubject, wherein the cancer cell comprises an activated serine-threoninekinase or wherein the subject is identified as being in need ofinhibition of a serine-threonine kinase for the treatment or preventionof cancer.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for inhibiting at leastone protein kinase or modulating (e.g., decreasing) the amount of atleast one protein kinase.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for inhibiting a proteintyrosine kinase or modulating (e.g., decreasing) the amount of at leastone protein tyrosine kinase.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for inhibiting aserine-threonine kinase or modulating (e.g., decreasing) the amount ofat least one serine-threonine kinase.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for treating orpreventing a disease (e.g., a disease in which one or more proteinkinases plays a role). In one aspect, the disease is protein kinasemediated disorder. In one aspect, the disease is a proliferative disease(e.g., a proliferative disease in which one or more protein kinases playa role). In some embodiments, the protein kinase is a protein tyrosinekinase. In other embodiments, the protein kinase is a serine-threoninekinase.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for treating orpreventing cancer in a subject, wherein the cancer cell comprises atleast one activated protein kinase or wherein the subject is identifiedas being in need of inhibition of at least one protein kinase for thetreatment or prevention of cancer.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for treating orpreventing cancer in a subject, wherein the cancer cell comprises anactivated protein tyrosine kinase or wherein the subject is identifiedas being in need of inhibition of a protein tyrosine kinase for thetreatment or prevention of cancer.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for treating orpreventing cancer in a subject, wherein the cancer cell comprises anactivated serine-threonine kinase or wherein the subject is identifiedas being in need of inhibition of a serine-threonine kinase for thetreatment or prevention of cancer.

The present application provides inhibitors of protein kinases that aretherapeutic agents in the treatment or prevention of diseases such ascancer and metastasis.

The present application further provides compounds and compositions withan improved efficacy and/or safety profile relative to known proteinkinase inhibitors. The present application also provides agents withnovel mechanisms of action toward protein kinases in the treatment ofvarious types of diseases including cancer and metastasis.

The compounds and methods of the present application address unmet needsin the treatment of diseases or disorders in which pathogenic oroncogenic endogenous proteins (e.g., protein kinases) play a role, suchas cancer.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, illustrative methods and materials are nowdescribed. In the case of conflict, the present specification, includingdefinitions, will control. In addition, the materials, methods, andexamples are illustrative only and are not intended to be limiting.Other features, objects, and advantages of the disclosure will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. The referencescited herein are not admitted to be prior art to the application.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a heatmap displaying viability (as approximated by ATPluminescence measurement using CellTiter-Glo assay) of various cellstreated with representative compounds of the present application, basedon results from 10-point dose-response experiments after 72 h treatmentwith the compounds. Experiments were performed in quadruplicates.

FIG. 2A-2N are graphs showing the percentage viability (relative toDMSO/vehicle controls) of various cells treated with Sunitinib, CompoundI-2, Compound I-7, Compound I-10, Compound I-11, Compound I-6, CompoundI-13, or Compound I-37: FIG. 2A: DNA41, FIG. 2B: HBP-ALL, FIG. 2C: HSB2,FIG. 2D: JURKAT, FIG. 2E: KOPTK1, FIG. 2F: MOLT4, FIG. 2G:MOLT4-CRBN^(−/−), FIG. 2H: MOLT16, FIG. 2I: CCRF-CEM, FIG. 2J:P12-ICHIKAWA, FIG. 2K: PF382, FIG. 2L: RPMI-8402 FIG. 2M: SKW3, and FIG.2N: SUPT11. The results were from 10-point dose-response experimentsafter 72 h treatment with the compounds. Experiments were performed inquadruplicates.

DETAILED DESCRIPTION Compounds of the Application

The present application relates to bifunctional compounds having utilityas modulators of ubiquitination and proteosomal degradation of targetedproteins, especially compounds comprising a moiety capable of binding toa polypeptide or a protein that is degraded and/or otherwise inhibitedby the bifunctional compounds of the present application. In particular,the present application is directed to compounds which contain a moiety,e.g., a small molecule moiety (e.g., having a molecular weight of below2,000, 1,000, 500, or 200 Daltons), such as a thalidomide-like moiety,which is capable of binding to an E3 ubiquitin ligase, such as cereblon,and a ligand that is capable of binding to a target protein, in such away that the target protein is placed in proximity to the ubiquitinligase to effect degradation (and/or inhibition) of that protein.

The compounds of the present application can be used in methods to treata variety of diseases including, but not limited to, metabolicdisorders, bone diseases (e.g., osteoporosis, Paget's Disease, etc.),inflammation (e.g., rheumatoid arthritis and other inflammatorydisorders) and cancer (e.g., solid tumors and leukemias, mediated by oneor more kinases (e.g., protein kinase), or by dysregulation of a kinase(e.g., protein kinase), including, among others, advanced cases andcases which are resistant to one or more other treatments.

In one embodiment, the present application provides a bifunctionalcompound of Formula X:

wherein:

the Targeting Ligand is capable of binding to at least one targetedprotein, such as a protein kinase;

the Linker is a group that covalently binds to the Targeting Ligand andthe Degron; and

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon).

In one embodiment, the present application provides a compound ofFormula I:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

R₁, R₂, R₃, R₄, X₁, n1, and n2 are each as defined herein;

the Linker is a group that covalently binds to

and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to at least one targetedproteins, such a protein kinase.

In another embodiment, the present application provides a compound ofFormula II:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

A, R₆, R₇, R₈, X₂, X₃, q1, and q2 are each as defined herein;

the Linker is a group that covalently binds to

and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to at least one targetedproteins, such a protein kinase.

In another embodiment, the present application provides a compound ofFormula III:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

B₁, B₂, R₁₂, R₁₃, R₁₄, and r1 are each as defined herein;

the Linker is a group that covalently binds to

and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to at least one targetedproteins, such a protein kinase.

In another embodiment, the present application provides a compound ofFormula IV:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

B₃, B₄, R₁₇, and R₁₈ are each as defined herein;

the Linker is a group that covalently binds to

and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to at least one targetedproteins, such a protein kinase.

In another embodiment, the present application provides a compound ofFormula V:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

B₅, R₂₁, R₂₂, R₂₃, R₂₄, Y₁, and s2 are each as defined herein;

the Linker is a group that covalently binds to

and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to at least one targetedproteins, such a protein kinase.

In another embodiment, the present application provides a compound ofFormula VI:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

B₆, B₇, R₂₇, R₂₈, R₂₉, R₃₀, X₄, s3, s4, and s5 are each as definedherein;

the Linker is a group that covalently binds to

and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to at least one targetedproteins, such a protein kinase.

The present application further relates to a Degron of Formula D1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein R₃₇,R₃₈, R₃₉, R₄₀, Y, Z₃, q, and v are each as defined herein, and theDegron covalently binds to a Linker via

The present application further relates to a Degron of Formula D2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein R₄₁,R₄₂, and q′ are each as defined herein, and the Degron covalently bindsto a Linker via

The present application further relates to a Linker of Formula L1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein p1, p2,p3, W, Q1, and Z₁ are each as defined herein, the Linker is covalentlybonded to a Degron via the

next to Q1, and covalently bonded to a Targeting Ligand via the

next to Z₁.

Targeting Ligand

Targeting Ligand (TL) (or target protein moiety or target protein ligandor ligand) is a small molecule which is capable of binding to a targetprotein of interest, such a protein kinase.

In one embodiment, a Targeting Ligand is a compound of Formula TL-I:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

X₁ is NR₅ or O;

each R₁ and each R₄ are independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

R₂ and R₃ are each independently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

R₅ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, or C(O)(C₁-C₄) alkyl;

n1 is 0, 1, 2 or 3; and

n2 is 0, 1, or 2;

wherein the Targeting Ligand is bonded to the Linker via the

next to

In some embodiments, X₁ is NR₅. In another embodiment, X₁ is O.

In some embodiments, each R₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₁ is independently halogen, OH, or NH₂. In other embodiments, eachR₁ is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, each R₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,or halogen. In other embodiments, each R₁ is independently (C₁-C₃) alkylor halogen. In other embodiments, each R₁ is independently methyl,ethyl, n-propyl, i-propyl, or halogen. In other embodiments, each R₁ isindependently methyl, ethyl, n-propyl, i-propyl, F, or Cl. In otherembodiments, each R₁ is independently F or Cl. In other embodiments, atleast one R₁ is F.

In some embodiments, R₂ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₂ is H or (C₁-C₄) alkyl. In other embodiments, R₂ isH, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₂ is H,methyl or ethyl. In other embodiments, R₂ is (C₁-C₄) alkyl. In otherembodiments, R₂ is methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R₂ is methyl or ethyl. In other embodiments, R₂ is (C₁-C₄)alkyl or (C₁-C₄) haloalkyl. In other embodiments, R₂ is H.

In some embodiments, R₃ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₃ is H or (C₁-C₄) alkyl. In other embodiments, R₃ isH, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₃ is H,methyl or ethyl. In other embodiments, R₃ is (C₁-C₄) alkyl. In otherembodiments, R₃ is methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R₃ is methyl or ethyl. In other embodiments, R₃ is (C₁-C₄)alkyl or (C₁-C₄) haloalkyl. In other embodiments, R₃ is H.

In some embodiments, each R₄ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₄ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₄ is independently halogen, OH, or NH₂. In other embodiments, eachR₄ is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, each R₄ is independently (C₁-C₃) alkyl or (C₁-C₃)haloalkyl. In other embodiments, each R₄ is independently methyl, ethyl,n-propyl, i-propyl, or (C₁-C₃) haloalkyl. In other embodiments, each R₄is independently methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, each R₄ is methyl or ethyl. In other embodiments, at leastone R₄ is methyl. In other embodiments, at least two R₄ are methyl.

In some embodiments, R₅ is H, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, orC(O)(C₁-C₃) alkyl. In other embodiments, R₅ is (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, or C(O)(C₁-C₃) alkyl. In other embodiments, R₅ is (C₁-C₃)haloalkyl or C(O)(C₁-C₃) alkyl. In other embodiments, R₅ is H or (C₁-C₃)alkyl. In other embodiments, R₅ is H, methyl, ethyl, n-propyl, ori-propyl. In other embodiments, R₅ is H, methyl, or ethyl. In otherembodiments, R₅ is H.

In some embodiments, n1 is 0. In other embodiments, n1 is 1. In otherembodiments, nl is 2. In other embodiments, n1 is 3. In otherembodiments, n1 is 0 or 1. In other embodiments, nl is 1 or 2. In otherembodiments, n1 is 2 or 3. In other embodiments, n1 is 0, 1, or 2. Inother embodiments, n1 is 1, 2, or 3.

In some embodiments, n2 is 0. In other embodiments, n2 is 1. In otherembodiments, n2 is 2. In other embodiments, n2 is 0 or 1. In otherembodiments, n2 is 1 or 2.

Any of the groups described herein for any of Xi, R₁, R₂, R₃, R₄, R₅,n1, and n2 can be combined with any of the groups described herein forone or more of the remainder of Xi, R₁, R₂, R₃, R₄, R₅, n1, and n2, andmay further be combined with any of the groups described herein for theLinker.

For a Targeting Ligand of Formula TL-I:

-   -   (1) In one embodiment, X₁ is NR₅ and R₅ is H.    -   (2) In one embodiment, X₁ is NR₅ and R₅ is (C₁-C₃) alkyl.    -   (3) In one embodiment, X₁ is NR₅ and R₅ is methyl.    -   (4) In one embodiment, X₁ is NR₅, R₅ is H, and R₃ is H.    -   (5) In one embodiment, X₁ is NR₅, R₅ is (C₁-C₃) alkyl, and R₃ is        H.    -   (6) In one embodiment, X₁ is NR₅, R₅ is methyl, and R₃ is H.    -   (7) In one embodiment, X₁ is NR₅, R₅ is H, R₃ is H, and R₂ is H.    -   (8) In one embodiment, X₁ is NR₅, R₅ is (C₁-C₃) alkyl, R₃ is H,        and R₂ is H.    -   (9) In one embodiment, X₁ is NR₅, R₅ is methyl, R₃ is H, and R₂        is H.    -   (10) In one embodiment, X₁ is NR₅, R₅ is H, R₃ is H, R₂ is H,        and at least one R₁ is halogen.    -   (11) In one embodiment, X₁ is NR₅, R₅ is H, R₃ is H, R₂ is H,        and at least one R₁ is F.    -   (12) In one embodiment, X₁ is NR₅, R₅ is (C₁-C₃) alkyl, R₃ is H,        R₂ is H, and at least one R₁ is halogen.    -   (13) In one embodiment, X₁ is NR₅, R₅ is (C₁-C₃) alkyl, R₃ is H,        R₂ is H, and at least one R₁ is F.    -   (14) In one embodiment, X₁ is NR₅, R₅ is methyl, R₃ is H, R₂ is        H, and at least one Ri is halogen.    -   (15) In one embodiment, X₁ is NR₅, R₅ is methyl, R₃ is H, R₂ is        H, and at least one Ri is F.    -   (16) In one embodiment, X₁ is NR₅ and R₃ is H.    -   (17) In one embodiment, X₁ is NR₅, R₃ is H, and R₂ is H.    -   (18) In one embodiment, X₁ is NR₅, R₃ is H, R₂ is H, and at        least one R₁ is halogen.    -   (19) In one embodiment, X₁ is NR₅, R₃ is H, R₂ is H, and at        least one R₁ is F.    -   (20) In one embodiment, X₁ is NR₅ and at least one R₁ is        halogen.    -   (21) In one embodiment, X₁ is NR₅ and at least one R₁ is F.    -   (22) In one embodiment, X₁ is NR₅ and R₂ is H.    -   (23) In one embodiment, X₁ is O and R₃ is H.    -   (24) In one embodiment, X₁ is O, R₃ is H, and R₂ is H.    -   (25) In one embodiment, X₁ is O, R₃ is H, R₂ is H, and at least        one R₁ is halogen.    -   (26) In one embodiment, X₁ is O, R₃ is H, R₂ is H, and at least        one R₁ is F.    -   (27) In one embodiment, X₁ is O, R₂ is H, and at least one R₁ is        halogen.    -   (28) In one embodiment, X₁ is O, R₂ is H, and at least one R₁ is        F.    -   (29) In one embodiment, X₁ is O and at least one R₁ is halogen.    -   (30) In one embodiment, X₁ is O and at least one R₁ is F.    -   (31) In one embodiment, X₁ is O and R₂ is H.    -   (32) In one embodiment, X₁ is O, R₂ is H, and at least one R₁ is        halogen.    -   (33) In one embodiment, X₁ is O, R₂ is H, and at least one R₁ is        F.    -   (34) In one embodiment, R₁, R₂, R₃, R₅, and X₁ are each as        defined, where applicable, in any one of (1)-(33), and n1 is 1.    -   (35) In one embodiment, R₁, R₂, R₃, R₅, and X₁ are each as        defined, where applicable, in any one of (1)-(33), and n1 is 2.    -   (36) In one embodiment, R₁, R₂, R₃, R₅, n1, and X₁ are each as        defined, where applicable, in any one of (1)-(35), and n2 is 1.    -   (37) In one embodiment, R₁, R₂, R₃, R₅, n1, and X₁ are each as        defined, where applicable, in any one of (1)-(35), and n2 is 2.    -   (38) In one embodiment, R₁, R₂, R₃, R₅, n1, n2, and X₁ are each        as defined, where applicable, in any one of (1)-(37), and each        R₄ is independently (C₁-C₃) alkyl.    -   (39) In one embodiment, R₁, R₂, R₃, R₅, n1, n2, and X₁ are each        as defined, where applicable, in any one of (1)-(37), and at        least one R₄ is methyl.

In one embodiment, the compound of Formula TL-I is of Formula TL-Ia:

wherein R₁, R₃, R₄, n1, and n2 are each as defined above in FormulaTL-I.

For a Targeting Ligand of Formula TL-Ia:

-   -   (1) In one embodiment, R₃ is H.    -   (2) In one embodiment, R₃ is H and at least one R₁ is halogen.    -   (3) In one embodiment, R₃ is H and at least one R₁ is F.    -   (4) In one embodiment, R₁ and R₃ are each as defined, where        applicable, in any one of (1)-(4), and n1 is 1.    -   (5) In one embodiment, R₁ and R₃ are each as defined, where        applicable, in any one of (1)-(4), and n1 is 2.    -   (6) In one embodiment, R₁ and R₃ are each as defined, where        applicable, in any one of (1)-(5), and n2 is 1.    -   (7) In one embodiment, R₁ and R₃ are each as defined, where        applicable, in any one of (1)-(5), and n2 is 2.    -   (8) In one embodiment, R₁, R₃, n1, and n2 are each as defined,        where applicable, in any one of (1)-(7), and each R₄ is        independently (C₁-C₃) alkyl.    -   (9) In one embodiment, R₁, R₃, n1, and n2 are each as defined,        where applicable, in any one of (1)-(7), and at least one R₄ is        methyl.

R₁, R₃, R₄, n1, and n2 can each be selected from any of the groups andcombined as described above in Formula TL-I or TL-Ia.

In another embodiment, a Targeting Ligand is a compound of FormulaTL-II:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

A is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, wherein the aryl or heteroarylare optionally substituted with one to three R₉;

X₂ is O, S, or NR₁₀;

X₃ is N or CR₁₁;

each R₆ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, NH₂, (C₁-C₄) alkylamino,(C₁-C₄) dialkylamino, NHS(O)₂(C₁-C₄) alkyl, or N((C₁-C₄)alkyl)S(O)₂(C₁-C₄) alkyl;

R₇ is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

each R₈ and each R₉ are independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

R₁₀ is H or (C₁-C₄) alkyl;

R₁₁ is (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, halogen, OH, or NH₂;

q1 is 0, 1, 2, 3, or 4; and

q2 is 0, 1, or 2;

wherein the Targeting Ligand is bonded to the Linker via the

next to A

In some embodiments, A is (C₆-C₁₀) aryl optionally substituted with oneto three R₉. In other embodiments, A is 5- or 6-membered heteroarylcomprising 1-3 heteroatoms selected from N, S, and O, optionallysubstituted with one to three R₉. In other embodiments, A is 5-memberedheteroaryl comprising 1-3 heteroatoms selected from N, S, and O,optionally substituted with one to three R₉. In other embodiments, A is6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, andO, optionally substituted with one to three R₉. In other embodiments, Ais phenyl optionally substituted with one to three R₉. In otherembodiments, A is phenyl.

In some embodiments, X₂ is S. In other embodiments, X₂ is NR₁₀. In otherembodiments, X₂ is O or NR₁₀. In other embodiments, X₂ is S or NR₁₀. Inother embodiments, X₂ is O or S. In other embodiments, X₂ is O.

In some embodiments, X₃ is N. In other embodiments, X₃ is CR₁₁.

In some embodiments, each R₆ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, NH₂, (C₁-C₃)alkylamino, (C₁-C₃) dialkylamino, NHS(O)₂(C₁-C₄) alkyl, or N((C₁-C₄)alkyl)S(O)₂(C₁-C₄) alkyl. In other embodiments, each R₆ is independently(C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy,halogen, OH, or NH₂. In other embodiments, each R₆ is independently(C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy.In other embodiments, each R₆ is independently halogen, OH, or NH₂. Inother embodiments, each R₆ is independently (C₁-C₃) alkoxy or (C₁-C₃)haloalkoxy. In other embodiments, each R₆ is independently halogen, OH,NH₂, (C₁-C₃) alkylamino, (C₁-C₃) dialkylamino, NHS(O)₂(C₁-C₄) alkyl orN((C₁-C₄) alkyl)S(O)₂(C₁-C₄) alkyl. In other embodiments, each R₆ isindependently OH, NH₂, (C₁-C₃) alkylamino, or (C₁-C₃) dialkylamino. Inother embodiments, each R₆ is independently NHS(O)₂(C₁-C₄) alkyl orN((C₁-C₄) alkyl)S(O)₂(C₁-C₄) alkyl. In other embodiments, each R₆ isindependently (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In other embodiments,each R₆ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen.In other embodiments, each R₆ is independently methyl, ethyl, n-propyl,i-propyl, or (C₁-C₃) haloalkyl. In other embodiments, each R₆ isindependently halogen, NHS(O)₂(C₁-C₄) alkyl, or N((C₁-C₄)alkyl)S(O)₂(C₁-C₄) alkyl. In other embodiments, each R₆ is independentlyhalogen or NHS(O)₂(C₁-C₄) alkyl. In other embodiments, each R₆ isindependently F, C₁, or NHS(O)₂(C₁-C₄) alkyl. In other embodiments, eachR₆ is independently F or NHS(O)₂(C₁-C₄) alkyl.

In some embodiments, R₇ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₇ is H or (C₁-C₄) alkyl. In other embodiments, R₇ isH, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₇ is H,methyl or ethyl. In other embodiments, R₇ is (C₁-C₄) alkyl. In otherembodiments, R₇ is methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R₇ is methyl or ethyl. In other embodiments, R₇ is (C₁-C₄)alkyl or (C₁-C₄) haloalkyl. In other embodiments, R₇ is H.

In some embodiments, each R₈ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₈ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₈ is independently halogen, OH, or NH₂. In other embodiments, eachR₈ is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, each R₈ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,or halogen. In other embodiments, each R₈ is independently (C₁-C₃) alkylor halogen. In other embodiments, each R₈ is independently methyl,ethyl, n-propyl, i-propyl, or halogen.

In some embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₉ is independently halogen, OH, or NH₂. In other embodiments, eachR₉ is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkylor halogen. In other embodiments, each R₉ is independently methyl,ethyl, n-propyl, i-propyl, or halogen.

In some embodiments, R₁₀ is H or (C₁-C₃) alkyl. In other embodiments,R₁₀ is (C₁-C₃) alkyl. In other embodiments, R₁₀ is methyl, ethyl,n-propyl, or i-propyl. In other embodiments, R₁₀ is methyl or ethyl. Inother embodiments, R₁₀ is H, methyl, or ethyl. In other embodiments, R₁₀is H.

In some embodiments, R₁₁ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments,R₁₁ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃)haloalkoxy. In other embodiments, R₁₁ is halogen, OH, or NH₂. In otherembodiments, R₁₁ is (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, R₁₁ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen. Inother embodiments, R₁₁ is (C₁-C₃) alkyl or halogen. In otherembodiments, R₁₁ is methyl, ethyl, n-propyl, i-propyl, or halogen.

In some embodiments, q1 is 0. In other embodiments, q1 is 1. In otherembodiments, q1 is 2. In other embodiments, q1 is 3. In otherembodiments, q1 is 4. In other embodiments, q1 is 0 or 1. In otherembodiments, q1 is 1 or 2. In other embodiments, q1 is 2 or 3. In otherembodiments, q1 is 3 or 4. In other embodiments, q1 is 0, 1, or 2. Inother embodiments, q1 is 1, 2, or 3. In other embodiments, q1 is 2, 3,or 4. In other embodiments, q1 is 0, 1, 2, or 3. In other embodiments,q1 is 1, 2, 3, or 4.

In some embodiments, q2 is 0. In other embodiments, q2 is 1. In otherembodiments, q2 is 2. In other embodiments, q2 is 0 or 1. In otherembodiments, q2 is 1 or 2.

Any of the groups described herein for any of A, X₂, X₃, R₆, R₇, R₈, R₉,R₁₀, R₁₁, q1, and q2 can be combined with any of the groups describedherein for one or more of the remainder of A, X₂, X₃, R₆, R₇, R₈, R₉,R₁₀, R₁₁, q1, and q2, and may further be combined with any of the groupsdescribed herein for the Linker.

For a Targeting Ligand of Formula TL-II:

-   -   (1) In one embodiment, X₂ is O and X₃ is N.    -   (2) In one embodiment, X₂ is O, X₃ is N, and A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉.    -   (3) In one embodiment, X₂ is O, X₃ is N, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, and R₇ is H.    -   (4) In one embodiment, X₂ is O, X₃ is N, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, R₇ is H, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (5) In one embodiment, X₂ is O, X₃ is N, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, and R₇ is (C₁-C₃)        alkyl.    -   (6) In one embodiment, X₂ is O, X₃ is N, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, R₇ is (C₁-C₃)        alkyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (7) In one embodiment, X₂ is O, X₃ is N, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, and R₇ is methyl.    -   (8) In one embodiment, X₂ is O, X₃ is N, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, R₇ is methyl, and        each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (9) In one embodiment, X₂ is O, X₃ is N, and A is phenyl        optionally substituted with one to three R₉.    -   (10) In one embodiment, X₂ is O, X₃ is N, A is phenyl optionally        substituted with one to three R₉, and R₇ is H.    -   (11) In one embodiment, X₂ is O, X₃ is N, A is phenyl optionally        substituted with one to three R₉, R₇ is H, and each R₆ is        independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (12) In one embodiment, X₂ is O, X₃ is N, A is phenyl optionally        substituted with one to three R₉, and R₇ is (C₁-C₃) alkyl.    -   (13) In one embodiment, X₂ is O, X₃ is N, A is phenyl optionally        substituted with one to three R₉, R₇ is (C₁-C₃) alkyl, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (14) In one embodiment, X₂ is O, X₃ is N, A is phenyl optionally        substituted with one to three R₉, and R₇ is methyl.    -   (15) In one embodiment, X₂ is O, X₃ is N, A is phenyl optionally        substituted with one to three R₉, R₇ is methyl, and each R₆ is        independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (16) In one embodiment, X₂ is O, X₃ is N, and A is phenyl.    -   (17) In one embodiment, X₂ is O, X₃ is N, A is phenyl, and R₇ is        H.    -   (18) In one embodiment, X₂ is O, X₃ is N, A is phenyl, R₇ is H,        and each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (19) In one embodiment, X₂ is O, X₃ is N, A is phenyl, and R₇ is        (C₁-C₃) alkyl.    -   (20) In one embodiment, X₂ is O, X₃ is N, A is phenyl, R₇ is        (C₁-C₃) alkyl, and each R₆ is independently halogen or        NHS(O)₂(C₁-C₄) alkyl.    -   (21) In one embodiment, X₂ is O, X₃ is N, A is phenyl, and R₇ is        methyl.    -   (22) In one embodiment, X₂ is O, X₃ is N, A is phenyl, R₇ is        methyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (23) In one embodiment, X₂ is O, X₃ is N, and A is 5- or        6-membered heteroaryl comprising 1-3 heteroatoms selected from        N, S, and O, optionally substituted with one to three R₉.    -   (24) In one embodiment, X₂ is O, X₃ is N, A is 5- or 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is H.    -   (25) In one embodiment, X₂ is O, X₃ is N, A is 5- or 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is H, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (26) In one embodiment, X₂ is O, X₃ is N, A is 5- or 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is (C₁-C₃)        alkyl.    -   (27) In one embodiment, X₂ is O, X₃ is N, A is 5- or 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is (C₁-C₃)        alkyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (28) In one embodiment, X₂ is O, X₃ is N, A is 5- or 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is methyl.    -   (29) In one embodiment, X₂ is O, X₃ is N, A is 5- or 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is methyl, and        each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (30) In one embodiment, X₂ is O, X₃ is N, and A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉.    -   (31) In one embodiment, X₂ is O, X₃ is N, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is H.    -   (32) In one embodiment, X₂ is O, X₃ is N, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is H, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (33) In one embodiment, X₂ is O, X₃ is N, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is (C₁-C₃)        alkyl.    -   (34) In one embodiment, X₂ is O, X₃ is N, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is (C₁-C₃)        alkyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (35) In one embodiment, X₂ is O, X₃ is N, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is methyl.    -   (36) In one embodiment, X₂ is O, X₃ is N, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is methyl, and        each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (37) In one embodiment, X₂ is O, X₃ is N, and A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉.    -   (38) In one embodiment, X₂ is O, X₃ is N, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is H.    -   (39) In one embodiment, X₂ is O, X₃ is N, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is H, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (40) In one embodiment, X₂ is O, X₃ is N, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is (C₁-C₃)        alkyl.    -   (41) In one embodiment, X₂ is O, X₃ is N, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is (C₁-C₃)        alkyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (42) In one embodiment, X₂ is O, X₃ is N, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is methyl.    -   (43) In one embodiment, X₂ is O, X₃ is N, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is methyl, and        each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (44) In one embodiment, X₂ is O and X₃ is CR₁₁.    -   (45) In one embodiment, X₂ is O, X₃ is CR₁₁, and A is (C₆-C₁₀)        aryl optionally substituted with one to three R₉.    -   (46) In one embodiment, X₂ is O, X₃ is CR₁₁, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, and R₇ is H.    -   (47) In one embodiment, X₂ is O, X₃ is CR₁₁, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, R₇ is H, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (48) In one embodiment, X₂ is O, X₃ is CR₁₁, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, and R₇ is (C₁-C₃)        alkyl.    -   (49) In one embodiment, X₂ is O, X₃ is CR₁₁, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, R₇ is (C₁-C₃)        alkyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (50) In one embodiment, X₂ is O, X₃ is CR₁₁, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, and R₇ is methyl.    -   (51) In one embodiment, X₂ is O, X₃ is CR₁₁, A is (C₆-C₁₀) aryl        optionally substituted with one to three R₉, R₇ is methyl, and        each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (52) In one embodiment, X₂ is O, X₃ is CR₁₁, and A is phenyl        optionally substituted with one to three R₉.    -   (53) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl        optionally substituted with one to three R₉, and R₇ is H.    -   (54) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl        optionally substituted with one to three R₉, R₇ is H, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (55) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl        optionally substituted with one to three R₉, and R₇ is (C₁-C₃)        alkyl.    -   (56) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl        optionally substituted with one to three R₉, R₇ is (C₁-C₃)        alkyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (57) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl        optionally substituted with one to three R₉, and R₇ is methyl.    -   (58) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl        optionally substituted with one to three R₉, R₇ is methyl, and        each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (59) In one embodiment, X₂ is O, X₃ is CR₁₁, and A is phenyl.    -   (60) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl, and R₇        is H.    -   (61) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl, R₇ is        H, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (62) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl, and R₇        is (C₁-C₃) alkyl.    -   (63) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl, R₇ is        (C₁-C₃) alkyl, and each R₆ is independently halogen or        NHS(O)₂(C₁-C₄) alkyl.    -   (64) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl, and R₇        is methyl.    -   (65) In one embodiment, X₂ is O, X₃ is CR₁₁, A is phenyl, R₇ is        methyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (66) In one embodiment, X₂ is O, X₃ is CR₁₁, and A is 5- or        6-membered heteroaryl comprising 1-3 heteroatoms selected from        N, S, and O, optionally substituted with one to three R₉.    -   (67) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5- or        6-membered heteroaryl comprising 1-3 heteroatoms selected from        N, S, and O, optionally substituted with one to three R₉, and R₇        is H.    -   (68) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5- or        6-membered heteroaryl comprising 1-3 heteroatoms selected from        N, S, and O, optionally substituted with one to three R₉, R₇ is        H, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (69) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5- or        6-membered heteroaryl comprising 1-3 heteroatoms selected from        N, S, and O, optionally substituted with one to three R₉, and R₇        is (C₁-C₃) alkyl.    -   (70) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5- or        6-membered heteroaryl comprising 1-3 heteroatoms selected from        N, S, and O, optionally substituted with one to three R₉, R₇ is        (C₁-C₃) alkyl, and each R₆ is independently halogen or        NHS(O)₂(C₁-C₄) alkyl.    -   (71) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5- or        6-membered heteroaryl comprising 1-3 heteroatoms selected from        N, S, and O, optionally substituted with one to three R₉, and R₇        is methyl.    -   (72) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5- or        6-membered heteroaryl comprising 1-3 heteroatoms selected from        N, S, and O, optionally substituted with one to three R₉, R₇ is        methyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (73) In one embodiment, X₂ is O, X₃ is CR₁₁, and A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉.    -   (74) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is H.    -   (75) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is H, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (76) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is (C₁-C₃)        alkyl.    -   (77) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is (C₁-C₃)        alkyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (78) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is methyl.    -   (79) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is methyl, and        each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (80) In one embodiment, X₂ is O, X₃ is CR₁₁, and A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉.    -   (81) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is H.    -   (82) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is H, and each        R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (83) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is (C₁-C₃)        alkyl.    -   (84) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is (C₁-C₃)        alkyl, and each R₆ is independently halogen or NHS(O)₂(C₁-C₄)        alkyl.    -   (85) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, and R₇ is methyl.    -   (86) In one embodiment, X₂ is O, X₃ is CR₁₁, A is 6-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₉, R₇ is methyl, and        each R₆ is independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (87) In one embodiment, A, R₆, R₇, X₂, and X₃ are each as        defined, where applicable, in any one of (1)-(86), and q1 is 1.    -   (88) In one embodiment, A, R₆, R₇, X₂, and X₃ are each as        defined, where applicable, in any one of (1)-(86), and q1 is 2.    -   (89) In one embodiment, A, R₆, R₇, X₂, and X₃ are each as        defined, where applicable, in any one of (1)-(86), and q1 is 3.    -   (90) In one embodiment, A, R₆, R₇, X₂, X₃, and q1 are each as        defined, where applicable, in any one of (1)-(89), and q2 is 0.    -   (91) In one embodiment, A, R₆, R₇, X₂, X₃, and q1 are each as        defined, where applicable, in any one of (1)-(89), and q2 is 1.    -   (92) In one embodiment, A, R₆, R₇, X₂, X₃, and q1 are each as        defined, where applicable, in any one of (1)-(89), and q2 is 2.

In one embodiment, the compound of Formula TL-II is of Formula TL-IIa:

wherein R₆, R₇, R₈, R₉, q1, and q2 are each as defined above in FormulaTL-II.

For a Targeting Ligand of Formula TL-IIa:

-   -   (1) In one embodiment, R₇ is H.    -   (2) In one embodiment, R₇ is (C₁-C₃) alkyl.    -   (3) In one embodiment, R₇ is methyl.    -   (4) In one embodiment, R₇ is H, and each R₆ is independently        halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (5) In one embodiment, R₇ is (C₁-C₃) alkyl, and each R₆ is        independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (6) In one embodiment, R₇ is methyl, and each R₆ is        independently halogen or NHS(O)₂(C₁-C₄) alkyl.    -   (7) In one embodiment, R₆ and R₇ are each as defined, where        applicable, in any one of(1)-(6), and q1 is 1.    -   (8) In one embodiment, R₆ and R₇ are each as defined, where        applicable, in any one of (1)-(6), and q1 is 2.    -   (9) In one embodiment, R₆ and R₇ are each as defined, where        applicable, in any one of (1)-(6), and q1 is 3.    -   (10) In one embodiment, R₆, R₇, and q1 are each as defined,        where applicable, in any one of (1)-(9), and q2 is 0.    -   (11) In one embodiment, R₆, R₇, and q1 are each as defined,        where applicable, in any one of (1)-(9), and q2 is 1.    -   (12) In one embodiment, R₆, R₇, and q1 are each as defined,        where applicable, in any one of (1)-(9), and q2 is 2.

R₆, R₇, R₈, R₉, q1, and q2 can each be selected from any of the groupsand combined as described above in Formula TL-II or TL-IIa.

In another embodiment, a Targeting Ligand is a compound of FormulaTL-III:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

B₁ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, wherein the aryl or heteroarylare optionally substituted with one to three R₁₅;

B₂ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, wherein the aryl or heteroarylare optionally substituted with one to three R₁₆;

R₁₂ is H or (C₁-C₄) alkyl;

each R₁₃ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

R₁₄ is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

each R₁₅ and each R₁₆ are independently (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; and

r1 is 0, 1, 2, 3 or 4;

wherein the Targeting Ligand is bonded to the Linker via the

next to

In some embodiments, B₁ is (C₆-C₁₀) aryl optionally substituted with oneto three R₁₅. In some embodiments, B₁ is (C₆-C₁₀) aryl substituted withone to three R₁₅. In other embodiments, B₁ is 5- or 6-memberedheteroaryl comprising 1-3 heteroatoms selected from N, S, and O,optionally substituted with one to three R₁₅. In other embodiments, B₁is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected fromN, S, and O, substituted with one to three R₁₅. In other embodiments, B₁is 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, S,and O, optionally substituted with one to three R₁₅. In otherembodiments, B₁ is 5-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, substituted with one to three R₁₅. In otherembodiments, B₁ is 6-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, optionally substituted with one to three R₁₅.In other embodiments, B₁ is 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, substituted with one to threeR₁₅. In other embodiments, B₁ is phenyl optionally substituted with oneto three R₁₅. In other embodiments, B₁ is phenyl substituted with one tothree R₁₅.

In some embodiments, B₂ is (C₆-C₁₀) aryl optionally substituted with oneto three R₁₆. In some embodiments, B₂ is (C₆-C₁₀) aryl substituted withone to three R₁₆. In other embodiments, B₂ is 5- or 6-memberedheteroaryl comprising 1-3 heteroatoms selected from N, S, and O,optionally substituted with one to three R₁₆. In other embodiments, B₂is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected fromN, S, and O, substituted with one to three R₁₆. In other embodiments, B₂is 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, S,and O, optionally substituted with one to three R₁₆. In otherembodiments, B₂ is 5-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, substituted with one to three R₁₆. In otherembodiments, B₂ is 6-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, optionally substituted with one to three R₁₆.In other embodiments, B₂ is 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, substituted with one to threeR₁₆. In other embodiments, B₂ is phenyl optionally substituted with oneto three R₁₆. In other embodiments, B₂ is phenyl substituted with one tothree R₁₆.

In some embodiments, R₁₂ is H or (C₁-C₃) alkyl. In other embodiments,R₁₂ is (C₁-C₃) alkyl. In other embodiments, R₁₂ is methyl, ethyl,n-propyl, or i-propyl. In other embodiments, R₁₂ is methyl or ethyl. Inother embodiments, R₁₂ is H, methyl, or ethyl. In other embodiments, R₁₂is H.

In some embodiments, each R₁₃ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₁₃ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₁₃ is independently halogen, OH, or NH₂. In other embodiments,each R₁₃ is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, each R₁₃ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,or halogen. In other embodiments, each R₁₃ is independently (C₁-C₃)alkyl or halogen. In other embodiments, each R₁₃ is independently(C₁-C₃) alkyl. In other embodiments, each R₁₃ is independently methyl,ethyl, n-propyl, i-propyl, or halogen. In other embodiments, each R₁₃ isindependently methyl, ethyl, n-propyl, i-propyl, F, or Cl. In otherembodiments, each R₁₃ is independently halogen. In other embodiments,each R₁₃ is independently F or Cl. In other embodiments, at least oneR₁₃ is Cl.

In some embodiments, R₁₄ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₁₄ is H or (C₁-C₄) alkyl. In other embodiments, R₁₄is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₁₄ isH, methyl or ethyl. In other embodiments, R₁₄ is (C₁-C₄) alkyl. In otherembodiments, R₁₄ is methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R₁₄ is methyl or ethyl. In other embodiments, R₁₄ is(C₁-C₄) alkyl or (C₁-C₄) haloalkyl. In other embodiments, R₁₄ is H.

In some embodiments, each R₁₅ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₁₅ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₁₅ is independently halogen, OH, or NH₂. In other embodiments,each R₁₅ is independently (C₁-C₃) alkyl or (C₁-C₃) alkoxy. In otherembodiments, each R₁₅ is independently (C₁-C₃) alkoxy or (C₁-C₃)haloalkoxy. In other embodiments, each R₁₅ is independently (C₁-C₃)alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, each R₁₅ isindependently (C₁-C₃) alkyl or halogen. In other embodiments, each R₁₅is independently methyl, ethyl, n-propyl, i-propyl, or halogen. In otherembodiments, each R₁₅ is independently (C₁-C₃) alkoxy. In otherembodiments, each R₁₅ is independently methoxy, ethoxy, n-propoxy, ori-propoxy. In other embodiments, each R₁₅ is independently methoxy orethoxy. In other embodiments, at least one R₁₅ is methoxy.

In some embodiments, each R₁₆ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₁₆ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₁₆ is independently halogen, OH, or NH₂. In other embodiments,each R₁₆ is independently (C₁-C₃) alkyl or (C₁-C₃) alkoxy. In otherembodiments, each R₁₆ is independently (C₁-C₃) alkoxy or (C₁-C₃)haloalkoxy. In other embodiments, each R₁₆ is independently (C₁-C₃)alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, each R₁₆ isindependently (C₁-C₃) alkyl or halogen. In other embodiments, each R₁₆is independently methyl, ethyl, n-propyl, i-propyl, or halogen. In otherembodiments, each R₁₆ is independently (C₁-C₃) alkoxy or halogen. Inother embodiments, each R₁₆ is independently methoxy, ethoxy, n-propoxy,i-propoxy, F, Cl, Br, or I. In other embodiments, each R₁₆ isindependently methoxy, ethoxy, n-propoxy, i-propoxy, F or Cl. In otherembodiments, each R₁₆ is independently methoxy or ethoxy. In otherembodiments, each R₁₆ is independently methoxy, ethoxy, Fl, or Cl.

In other embodiments, each R₁₆ is independently methoxy or F. In otherembodiments, at least one R₁₆ is methoxy and at least one R₁₆ is F.

In some embodiments, r1 is 0. In other embodiments, r1 is 1. In otherembodiments, rl is 2. In other embodiments, r1 is 3. In otherembodiments, r1 is 4. In other embodiments, r1 is 0 or 1. In otherembodiments, r1 is 1 or 2. In other embodiments, r1 is 2 or 3. In otherembodiments, r1 is 3 or 4. In other embodiments, r1 is 0, 1, or 2. Inother embodiments, r1 is 1, 2, or 3. In other embodiments, r1 is 2, 3,or 4.

Any of the groups described herein for any of B₁, B₂, R₁₂, R₁₃, R₁₄,R₁₅, R₁₆, and r1 can be combined with any of the groups described hereinfor one or more of the remainder of B₁, B₂, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, andr1, and may further be combined with any of the groups described hereinfor the Linker.

For a Targeting Ligand of Formula TL-III:

-   -   (1) In one embodiment, R₁₂ is H and R₁₄ is H.    -   (2) In one embodiment, R₁₂ is H, R₁₄ is H, and B₁ is (C₆-C₁₀)        aryl optionally substituted with one to three R₁₅.    -   (3) In one embodiment, R₁₂ is H, R₁₄ is H, and B₁ is phenyl        optionally substituted with one to three R₁₅.    -   (4) In one embodiment, R₁₂ is H, R₁₄ is H, and B₁ is (C₆-C₁₀)        aryl substituted with one to three R₁₅.    -   (5) In one embodiment, R₁₂ is H, R₁₄ is H, and B₁ is phenyl        substituted with one to three R₁₅.    -   (6) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is (C₆-C₁₀) aryl        optionally substituted with one to three R₁₅, and B₂ is (C₆-C₁₀)        aryl optionally substituted with one to three R₁₆.    -   (7) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is phenyl        optionally substituted with one to three R₁₅, and B₂ is (C₆-C₁₀)        aryl optionally substituted with one to three R₁₆.    -   (8) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is (C₆-C₁₀) aryl        optionally substituted with one to three R₁₅, and B₂ is phenyl        optionally substituted with one to three R₁₆.    -   (9) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is phenyl        optionally substituted with one to three R₁₅, and B₂ is phenyl        optionally substituted with one to three R₁₆.    -   (10) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is (C₆-C₁₀) aryl        substituted with one to three R₁₅, and B₂ is (C₆-C₁₀) aryl        optionally substituted with one to three R₁₆.    -   (11) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is phenyl        substituted with one to three R₁₅, and B₂ is (C₆-C₁₀) aryl        optionally substituted with one to three R₁₆.    -   (12) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is (C₆-C₁₀) aryl        substituted with one to three R₁₅, and B₂ is phenyl optionally        substituted with one to three R₁₆.    -   (13) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is phenyl        substituted with one to three R₁₅, and B₂ is phenyl optionally        substituted with one to three R₁₆.    -   (14) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is (C₆-C₁₀) aryl        substituted with one to three R₁₅, and B₂ is (C₆-C₁₀) aryl        substituted with one to three R₁₆.    -   (15) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is phenyl        substituted with one to three R₁₅, and B₂ is (C₆-C₁₀) aryl        substituted with one to three R₁₆.    -   (16) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is (C₆-C₁₀) aryl        substituted with one to three R₁₅, and B₂ is phenyl substituted        with one to three R₁₆.    -   (17) In one embodiment, R₁₂ is H, R₁₄ is H, B₁ is phenyl        substituted with one to three R₁₅, and B₂ is phenyl substituted        with one to three R₁₆.    -   (18) In one embodiment, B₁, B₂, R₁₂, and R₁₄ are each as        defined, where applicable, in any one of (1)-(17), and at least        one R₁₃ is halogen.    -   (19) In one embodiment, B₁, B₂, R₁₂, and R₁₄ are each as        defined, where applicable, in any one of (1)-(17), and at least        one R₁₃ is Cl.    -   (20) In one embodiment, B₁, B₂, R₁₂, R₁₃, and R₁₄ are each as        defined, where applicable, in any one of (1)-(19), and r1 is 0.    -   (21) In one embodiment, B₁, B₂, R₁₂, R₁₃, and R₁₄ are each as        defined, where applicable, in any one of (1)-(19), and r1 is 1.    -   (22) In one embodiment, B₁, B₂, R₁₂, R₁₃, and R₁₄ are each as        defined, where applicable, in any one of (1)-(19), and r1 is 2.    -   (23) In one embodiment, B₁, B₂, R₁₂, R₁₃, R₁₄, and r1 are each        as defined, where applicable, in any one of (1)-(22), and at        least one R₁₅ is (C₁-C₃) alkoxy.    -   (24) In one embodiment, B₁, B₂, R₁₂, R₁₃, R₁₄, and r1 are each        as defined, where applicable, in any one of (1)-(22), and at        least one R₁₅ is methoxy.    -   (25) In one embodiment, B₁, B₂, R₁₂, R₁₃, R₁₄, R₁₅, and r1 are        each as defined, where applicable, in any one of (1)-(24), and        at least one R₁₆ is (C₁-C₃) alkoxy or halogen.    -   (26) In one embodiment, B₁, B₂, R₁₂, R₁₃, R₁₄, R₁₅, and r1 are        each as defined, where applicable, in any one of (1)-(24), and        at least one R₁₆ is methoxy or halogen.    -   (27) In one embodiment, B₁, B₂, R₁₂, R₁₃, R₁₄, R₁₅, and r1 are        each as defined, where applicable, in any one of (1)-(24), and        each R₁₆ is independently methoxy or F.    -   (28) In one embodiment, B₁, B₂, R₁₂, R₁₃, R₁₄, R₁₅, and r1 are        each as defined, where applicable, in any one of (1)-(24), and        at least one R₁₆ is methoxy and at least one R₁₆ is F.

In one embodiment, the compound of Formula TL-III is of Formula TL-IIIa:

wherein R₁₃, R₁₅, R₁₆, and r1 are each as defined above in FormulaTL-III.

For a Targeting Ligand of Formula TL-IIIa:

-   -   (1) In one embodiment, at least one R₁₃ is halogen.    -   (2) In one embodiment, at least one R₁₃ is Cl.    -   (3) In one embodiment, R₁₃ is halogen and r1 is 1.    -   (4) In one embodiment, R₁₃ is C₁ and r1 is 1.    -   (5) In one embodiment, at least one R₁₃ is halogen and r1 is 2.    -   (6) In one embodiment, at least one R₁₃ is C₁ and r1 is 2.    -   (7) In one embodiment, R₁₃ and r1 are each as defined, where        applicable, in any one of (1)-(6), and at least one R₁₅ is        (C₁-C₃) alkoxy.    -   (8) In one embodiment, R₁₃ and r1 are each as defined, where        applicable, in any one of (1)-(6), and at least one R₁₅ is        methoxy.    -   (9) In one embodiment, R₁₃, R₁₅, and r1 are each as defined,        where applicable, in any one of (1)-(8), and at least one R₁₆ is        (C₁-C₃) alkoxy or halogen.    -   (10) In one embodiment, R₁₃, R₁₅, and r1 are each as defined,        where applicable, in any one of (1)-(8), and at least one R₁₆ is        methoxy or halogen.    -   (11) In one embodiment, R₁₃, R₁₅, and r1 are each as defined,        where applicable, in any one of (1)-(8), and at least one R₁₆ is        methoxy or F.    -   (12) In one embodiment, R₁₃, R₁₅, and r1 are each as defined,        where applicable, in any one of (1)-(8), and at least one R₁₆ is        methoxy and at least one R₁₆ is F.

R₁₃, R₁₅, R₁₆, and r1 can each be selected from any of the groups andcombined as described above in Formula TL-III or TL-IIIa.

In another embodiment, a Targeting Ligand is a compound of FormulaTL-IV:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

B₃ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, wherein the aryl or heteroarylare optionally substituted with one to three R₁₉;

B₄ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, wherein the aryl or heteroarylare optionally substituted with one to three R₂₀;

R₁₇ is H or (C₁-C₄) alkyl;

R₁₈ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, halogen, OH, or NH₂; or

each R₁₉ and each R₂₀ are independently (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

wherein the Targeting Ligand is bonded to the Linker via the

next to

In some embodiments, B₃ is (C₆-C₁₀) aryl optionally substituted with oneto three R₁₉. In some embodiments, B₃ is (C₆-C₁₀) aryl substituted withone to three R₁₉. In other embodiments, B₃ is 5- or 6-memberedheteroaryl comprising 1-3 heteroatoms selected from N, S, and O,optionally substituted with one to three R₁₉. In other embodiments, B₃is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected fromN, S, and O, substituted with one to three R₁₉. In other embodiments, B₃is 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, S,and O, optionally substituted with one to three R₁₉. In otherembodiments, B₃ is 5-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, substituted with one to three R₁₉. In otherembodiments, B₃ is 6-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, optionally substituted with one to three R₁₉.In other embodiments, B₃ is 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, substituted with one to threeR₁₉. In other embodiments, B₃ is phenyl optionally substituted with oneto three R₁₉. In other embodiments, B₃ is phenyl.

In some embodiments, B₄ is (C₆-C₁₀) aryl optionally substituted with oneto three R₂₀. In some embodiments, B₄ is (C₆-C₁₀) aryl substituted withone to three R₂₀. In other embodiments, B₄ is 5- or 6-memberedheteroaryl comprising 1-3 heteroatoms selected from N, S, and O,optionally substituted with one to three R₂₀. In other embodiments, B₄is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected fromN, S, and O, substituted with one to three R₂₀. In other embodiments, B₄is 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, S,and O, optionally substituted with one to three R₂₀. In otherembodiments, B₄ is 5-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, substituted with one to three R₂₀. In otherembodiments, B₄ is 6-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, optionally substituted with one to three R₂₀.In other embodiments, B₄ is 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, substituted with one to threeR₂₀. In other embodiments, B₄ is phenyl optionally substituted with oneto three R₂₀. In other embodiments, B₄ is phenyl substituted with one tothree R₂₀. In other embodiments, B₄ is phenyl substituted with one ortwo R₂₀.

In some embodiments, R₁₇ is H or (C₁-C₃) alkyl. In other embodiments,R₁₇ is (C₁-C₃) alkyl. In other embodiments, R₁₇ is methyl, ethyl,n-propyl, or i-propyl. In other embodiments, R₁₇ is methyl or ethyl. Inother embodiments, R₁₇ is H, methyl, or ethyl. In other embodiments, R₁₇is H.

In some embodiments, R₁₈ is H, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments,R₁₈ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkoxy, halogen, OH, or NH₂. In other embodiments, R₁₈ is H, (C₁-C₃)alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. Inother embodiments, R₁₈ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₁₈ is (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, R₁₈ is H or (C₁-C₃) alkyl. In other embodiments, R₁₈ is H,methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₁₈ ismethyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₁₈ is H.

In some embodiments, each R₁₉ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₁₉ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₁₉ is independently halogen, OH, or NH₂. In other embodiments,each R₁₉ is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, each R₁₉ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,or halogen. In other embodiments, each R₁₉ is independently (C₁-C₃)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl) or halogen.

In some embodiments, each R₂₀ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₂₀ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₂₀ is independently halogen, OH, or NH₂. In other embodiments,each R₂₀ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen.In other embodiments, each R₂₀ is independently (C₁-C₃) alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl) or halogen. In other embodiments,each R₂₀ is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, each R₂₀ is independently (C₁-C₂) alkoxy or (C₁-C₂)haloalkoxy. In other embodiments, each R₂₀ is independently (C₁-C₃)haloalkoxy. In other embodiments, each R₂₀ is independently OCF₃, OCF₂,or OCH₂F. In other embodiments, at least one R₂₀ is OCF₃.

Any of the groups described herein for any of B₃, B₄, R₁₇, R₁₈, R₁₉, andR₂₀ can be combined with any of the groups described herein for one ormore of the remainder of B₃, B₄, R₁₇, R₁₈, R₁₉, and R₂₀, and may furtherbe combined with any of the groups described herein for the Linker.

For a Targeting Ligand of Formula TL-IV:

-   -   (1) In one embodiment, R₁₇ is H and R₁₈ is H.    -   (2) In one embodiment, R₁₇ is H, R₁₈ is H, and B₃ is (C₆-C₁₀)        aryl optionally substituted with one to three R₁₉.    -   (3) In one embodiment, R₁₇ is H, R₁₈ is H, and B₃ is phenyl        optionally substituted with one to three R₁₉.    -   (4) In one embodiment, R₁₇ is H, R₁₈ is H, and B₃ is phenyl.    -   (5) In one embodiment, R₁₇ is methyl and R₁₈ is H.    -   (6) In one embodiment, R₁₇ is methyl, R₁₈ is H, and B₃ is        (C₆-C₁₀) aryl optionally substituted with one to three R₁₉.    -   (7) In one embodiment, R₁₇ is methyl, R₁₈ is H, and B₃ is phenyl        optionally substituted with one to three R₁₉.    -   (8) In one embodiment, R₁₇ is methyl, R₁₈ is H, and B₃ is        phenyl.    -   (9) In one embodiment, B₃ is (C₆-C₁₀) aryl and B₄ is (C₆-C₁₀)        aryl substituted with one or two R₂₀.    -   (10) In one embodiment, B₃ is (C₆-C₁₀) aryl optionally        substituted with one to three R₁₉ and B₄ is (C₆-C₁₀) aryl        substituted with one or two R₂₀.    -   (11) In one embodiment, B₃ is (C₆-C₁₀) aryl optionally        substituted with one to three R₁₉ and B₄ is phenyl substituted        with one or two R₂₀.    -   (12) In one embodiment, B₃ is phenyl optionally substituted with        one to three R₁₉ and B₄ is phenyl substituted with one or two        R₂₀.    -   (13) In one embodiment, B₃ is phenyl and B₄ is phenyl        substituted with one or two R₂₀.    -   (14) In one embodiment, B₃ is 5- or 6-membered heteroaryl        comprising 1-3 heteroatoms selected from N, S, and O, optionally        substituted with one to three R₁₉, and B₄ is (C₆-C₁₀) aryl        substituted with one or two R₂₀.    -   (15) In one embodiment, B₃ is 5- or 6-membered heteroaryl        comprising 1-3 heteroatoms selected from N, S, and O and B₄ is        (C₆-C₁₀) aryl substituted with one or two R₂₀.    -   (16) In one embodiment, B₃ is 5-membered heteroaryl comprising        1-3 heteroatoms selected from N, S, and O, optionally        substituted with one to three R₁₉, and B₄ is (C₆-C₁₀) aryl        substituted with one or two R₂₀.    -   (17) In one embodiment, B₃ is 5-membered heteroaryl comprising        1-3 heteroatoms selected from N, S, and O and B₄ is (C₆-C₁₀)        aryl substituted with one or two R₂₀.    -   (18) In one embodiment, B₃ is 6-membered heteroaryl comprising        1-3 heteroatoms selected from N, S, and O, optionally        substituted with one to three R₁₉, and B₄ is (C₆-C₁₀) aryl        substituted with one or two R₂₀.    -   (19) In one embodiment, B₃ is 6-membered heteroaryl comprising        1-3 heteroatoms selected from N, S, and O and B₄ is (C₆-C₁₀)        aryl substituted with one or two R₂₀.    -   (20) In one embodiment, B₃, B₄, R₁₇, and R₁₈ are each as        defined, where applicable, in any one of (1)-(19), and at least        one R₂₀ is (C₁-C₄) haloalkoxy.    -   (21) In one embodiment, B₃, B₄, R₁₇, and R₁₈ are each as        defined, where applicable, in any one of (1)-(19), and at least        one R₂₀ is (C₁-C₂) haloalkoxy.    -   (22) In one embodiment, B₃, B₄, R₁₇, and R₁₈ are each as        defined, where applicable, in any one of (1)-(19), and at least        one R₂₀ is OCF3.    -   (23) In one embodiment, B₃ and B₄ are each as defined, where        applicable, in any one of (9)-(22), and R₁₇ is H.    -   (24) In one embodiment, B₃ and B₄ are each as defined, where        applicable, in any one of (9)-(22), and R₁₇ is methyl.    -   (25) In one embodiment, B₃ and B₄ are each as defined, where        applicable, in any one of (9)-(24), and R₁₈ is H.    -   (26) In one embodiment, B₃ and B₄ are each as defined, where        applicable, in any one of (9)-(24), and R₁₈ is methyl.

In one embodiment, the compound of Formula TL-IV is of Formula TL-IVa:

wherein R₁₉ and R₂₀ are each as defined above in Formula TL-IV.

For a Targeting Ligand of Formula TL-IVa:

-   -   (1) In one embodiment, at least one R₂₀ is (C₁-C₂) haloalkoxy.    -   (2) In one embodiment, at least one R₂₀ is (C₁-C₂) haloalkoxy.    -   (3) In one embodiment, at least one R₂₀ is OCF₃.

R₁₉ and R₂₀ can each be selected from any of the groups and combined asdescribed above in Formula TL-IV or TL-IVa.

In another embodiment, a Targeting Ligand is a compound of Formula TL-V:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

B₅ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, wherein the aryl or heteroarylare optionally substituted with one to three R₂₆;

Y₁ is C(O)NR₂₅ or NR₂₅C(O);

R₂₁ is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

R₂₂ and R₂₃ are each independently H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

each R₂₄ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, or C(O)(C₁-C₄) alkyl;

R₂₅ is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

each R₂₆ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; and

s2 is 0, 1, 2, or 3;

wherein the Targeting Ligand is bonded to the Linker via the

next to

In some embodiments, B₅ is (C₆-C₁₀) aryl optionally substituted with oneto three R₂₆. In some embodiments, B₅ is (C₆-C₁₀) aryl substituted withone to three R₂₆. In other embodiments, B₅ is 5- or 6-memberedheteroaryl comprising 1-3 heteroatoms selected from N, S, and O,optionally substituted with one to three R₂₆. In other embodiments, B₅is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected fromN, S, and O, substituted with one to three R₂₆. In other embodiments, B₅is 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, S,and O, optionally substituted with one to three R₂₆. In otherembodiments, B₅ is 5-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, substituted with one to three R₂₆. In otherembodiments, B₅ is 6-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, optionally substituted with one to three R₂₆.In other embodiments, B₅ is 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, substituted with one to threeR₂₆. In other embodiments, B₅ is phenyl optionally substituted with oneto three R₂₆. In other embodiments, B₅ is phenyl substituted with one tothree R₂₆. In other embodiments, B₅ is phenyl substituted with one ortwo R₂₆.

In some embodiments, Y₁ is C(O)NR₂₅. In other embodiments, Y₁ isNR₂₅C(O).

In some embodiments, R₂₁ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₂₁ is (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In otherembodiments, R₂₁ is H or (C₁-C₃) alkyl. In other embodiments, R₂₁ is(C₁-C₃) alkyl. In other embodiments, R₂₁ is methyl, ethyl, n-propyl, ori-propyl. In other embodiments, R₂₁ is H.

In some embodiments, R₂₂ is H, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments,R₂₂ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkoxy, halogen, OH, or NH₂. In other embodiments, R₂₂ is H, (C₁-C₃)alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. Inother embodiments, R₂₂ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₂₂ is (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. Inother embodiments, R₂₂ is H or (C₁-C₃) alkyl. In other embodiments, R₂₂is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₂₂ ismethyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₂₂ is H. Inother embodiments, R₂₂ is methyl or ethyl. In other embodiments, R₂₂ ismethyl.

In some embodiments, R₂₃ is H, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments,R₂₃ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkoxy, halogen, OH, or NH₂. In other embodiments, R₂₃ is H, (C₁-C₃)alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. Inother embodiments, R₂₃ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₂₃ is (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. Inother embodiments, R₂₃ is H or (C₁-C₃) alkyl. In other embodiments, R₂₃is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₂₃ ismethyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₂₃ is H.

In some embodiments, each R₂₄ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, or C(O)(C₁-C₃)alkyl. In other embodiments, each R₂₄ is independently (C₁-C₃) alkyl,(C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In otherembodiments, each R₂₄ is independently (C₁-C₃) alkyl or (C₁-C₃)haloalkyl. In other embodiments, each R₂₄ is independently (C₁-C₃)alkoxy or (C₁-C₃) haloalkoxy. In other embodiments, each R₂₄ isindependently halogen or C(O)(C₁-C₃) alkyl. In other embodiments, eachR₂₄ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, halogen, orC(O)(C₁-C₃) alkyl. In other embodiments, each R₂₄ is independently(C₁-C₃) alkyl, halogen, or C(O)(C₁-C₃) alkyl. In other embodiments, eachR₂₄ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or C(O)(C₁-C₃)alkyl.

In some embodiments, R₂₅ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₂₅ is (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In otherembodiments, R₂₅ is H or (C₁-C₃) alkyl. In other embodiments, R₂₅ is(C₁-C₃) alkyl. In other embodiments, R₂₅ is methyl, ethyl, n-propyl, ori-propyl. In other embodiments, R₂₅ is H.

In some embodiments, each R₂₆ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₂₆ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₂₆ is independently halogen, OH, or NH₂. In other embodiments,each R₂₆ is independently (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In otherembodiments, each R₂₆ is independently (C₁-C₃) alkoxy or (C₁-C₃)haloalkoxy. In other embodiments, each R₂₆ is independently (C₁-C₃)alkyl or halogen. In other embodiments, each R₂₆ is independentlymethyl, ethyl, n-propyl, i-propyl, F, C₁, Br, or I. In otherembodiments, each R₂₆ is independently methyl, ethyl, n-propyl,i-propyl, F or Cl. In other embodiments, each R₂₆ is independentlymethyl, ethyl, n-propyl, i-propyl, or Cl. In other embodiments, each R₂₆is independently methyl, ethyl, or Cl. In other embodiments, each R₂₆ isindependently methyl or Cl. In other embodiments, at least one R₂₆ ismethyl and at least one R₂₆ is Cl.

In some embodiments, s2 is 0. In other embodiments, s2 is 1. In otherembodiments, s2 is 2. In other embodiments, s2 is 3. In otherembodiments, s2 is 0 or 1. In other embodiments, s2 is 1 or 2. In otherembodiments, s2 is 2 or 3. In other embodiments, s2 is 0, 1, or 2. Inother embodiments, s2 is 1, 2, or 3.

Any of the groups described herein for any of Bs, Y₁, R₂₁, R₂₂, R₂₃,R₂₄, R₂₅, R₂₆, and s2 can be combined with any of the groups describedherein for one or more of the remainder of Bs, Y₁, R₂₁, R₂₂, R₂₃, R₂₄,R₂₅, R₂₆, and s2, and may further be combined with any of the groupsdescribed herein for the Linker.

For a Targeting Ligand of Formula TL-V:

-   -   (1) In one embodiment, R₂₁ is H and R₂₃ is H.    -   (2) In one embodiment, R₂₁ is methyl and R₂₃ is H.    -   (3) In one embodiment, R₂₁ is H and R₂₃ is methyl.    -   (4) In one embodiment, R₂₁ is methyl and R₂₃ is methyl.    -   (5) In one embodiment, R₂₁ is H and R₂₂ is H.    -   (6) In one embodiment, R₂₁ is methyl and R₂₂ is H.    -   (7) In one embodiment, R₂₁ is H and R₂₂ is methyl.    -   (8) In one embodiment, R₂₁ is methyl and R₂₂ is methyl.    -   (9) In one embodiment, R₂₁ is H, R₂₃ is H, and R₂₂ is methyl.    -   (10) In one embodiment, R₂₁ is methyl, R₂₃ is H, and R₂₂ is        methyl.    -   (11) In one embodiment, Y₁ is C(O)NR₂₅ and R₂₅ is H.    -   (12) In one embodiment, Y₁ is NR₂₅C(O) and R₂₅ is H.    -   (13) In one embodiment, Y₁ is C(O)NR₂₅, R₂₅ is H, and R₂₁ is H.    -   (14) In one embodiment, Y₁ is NR₂₅C(O), R₂₅ is H, and R₂₁ is H.    -   (15) In one embodiment, Y₁ is C(O)NR₂₅, R₂₅ is H, and R₂₃ is H.    -   (16) In one embodiment, Y₁ is NR₂₅C(O), R₂₅ is H, and R₂₃ is H.    -   (17) In one embodiment, Y₁ is C(O)NR₂₅, R₂₅ is H, and R₂₂ is        methyl.    -   (18) In one embodiment, Y₁ is NR₂₅C(O), R₂₅ is H, and R₂₂ is        methyl.    -   (19) In one embodiment, Y₁ is C(O)NR₂₅ and Bs is (C₆-C₁₀) aryl        optionally substituted with one to three R₂₆.    -   (20) In one embodiment, Y₁ is NR₂₅C(O) and B₅ is (C₆-C₁₀) aryl        optionally substituted with one to three R₂₆.    -   (21) In one embodiment, Y₁ is C(O)NR₂₅ and B₅ is (C₆-C₁₀) aryl        substituted with one to three R₂₆.    -   (22) In one embodiment, Y₁ is NR₂₅C(O) and Bs is (C₆-C₁₀) aryl        substituted with one to three R₂₆.    -   (23) In one embodiment, Y₁ is C(O)NR₂₅ and Bs is phenyl        optionally substituted with one to three R₂₆.    -   (24) In one embodiment, Y₁ is NR₂₅C(O) and B₅ is phenyl        optionally substituted with one to three R₂₆.    -   (25) In one embodiment, Y₁ is C(O)NR₂₅ and Bs is phenyl        substituted with one to three R₂₆.    -   (26) In one embodiment, Y₁ is NR₂₅C(O) and Bs is phenyl        substituted with one to three R₂₆.    -   (27) In one embodiment, R₂₁, R₂₂, and R₂₃ are each as defined,        where applicable, in any one of (1)-(10), and Y₁ is C(O)NR₂₅.    -   (28) In one embodiment, R₂₁, R₂₂, and R₂₃ are each as defined,        where applicable, in any one of (1)-(10), and Y₁ is NR₂₅C(O).    -   (29) In one embodiment, R₂₁, R₂₂, R₂₃, and Yiare each as        defined, where applicable, in any one of (1)-(10) and (27)-(28),        and R₂₅ is H.    -   (30) In one embodiment, Y₁ and Bs are each as defined, where        applicable, in any one of (19)-(26), and R₂₅ is H    -   (31) In one embodiment, Y₁, Bs, and R₂₅ are each as defined,        where applicable, in any one of (19)-(26) and (29)-(30), and R₂₁        is H.    -   (32) In one embodiment, Y₁, Bs, and R₂₅ are each as defined,        where applicable, in any one of (19)-(26) and (29)-(30), and R₂₁        is methyl.    -   (33) In one embodiment, Y₁, Bs, R₂₁, and R₂₅ are each as        defined, where applicable, in any one of (19)-(26) and        (29)-(32), and R₂₃ is H.    -   (34) In one embodiment, Y₁, Bs, R₂₁, R₂₃, and R₂₅ are each as        defined, where applicable, in any one of (19)-(26) and        (29)-(33), and R₂₂ is methyl.    -   (35) In one embodiment, Y₁, Bs, R₂₁, R₂₃, and R₂₅ are each as        defined, where applicable, in any one of (19)-(26) and        (29)-(33), and R₂₂ is H.    -   (36) In one embodiment, Y₁, Bs, R₂₁, R₂₂, R₂₃, and R₂₅ are each        as defined, where applicable, in any one of (19)-(26) and        (29)-(35), and R₂₆ is (C₁-C₄) alkyl or halogen.    -   (37) In one embodiment, Y₁, Bs, R₂₁, R₂₂, R₂₃, and R₂₅ are each        as defined, where applicable, in any one of (19)-(26) and        (29)-(35), and R₂₆ is methyl or Cl.    -   (38) In one embodiment, Y₁, Bs, R₂₁, R₂₂, R₂₃, R₂₅, and R₂₆ are        each as defined, where applicable, in any one of (1)-(37), and        s2 is 0.    -   (39) In one embodiment, Y₁, Bs, R₂₁, R₂₂, R₂₃, R₂₅, and R₂₆ are        each as defined, where applicable, in any one of (1)-(37), and        s2 is 1.

In one embodiment, the compound of Formula TL-V is of Formula TL-Va:

wherein R₂₁, R₂₂, R₂₅, and R₂₆ are each as defined above in FormulaTL-V.

For a Targeting Ligand of Formula TL-Va:

-   -   (1) In one embodiment, R₂₁ is H and R₂₂ is H.    -   (2) In one embodiment, R₂₁ is methyl and R₂₂ is H.    -   (3) In one embodiment, R₂₁ is H and R₂₂ is methyl.    -   (4) In one embodiment, R₂₁ is methyl and R₂₂ is methyl.    -   (5) In one embodiment, R₂₅ is H.    -   (6) In one embodiment, R₂₅ is H and R₂₁ is H.    -   (7) In one embodiment, R₂₅ is H and R₂₁ is methyl.    -   (8) In one embodiment, R₂₅ is H, R₂₁ is H, and R₂₂ is methyl.    -   (9) In one embodiment, R₂₅ is H, R₂₁ is methyl, and R₂₂ is        methyl.    -   (10) In one embodiment, R₂₅ is H, R₂₁ is H, and R₂₂ is H.    -   (11) In one embodiment, R₂₅ is H, R₂₁ is methyl, and R₂₂ is H.    -   (12) In one embodiment, R₂₁, R₂₂, and R₂₅ are each as defined,        where applicable, in any one of (1)-(11), and at least one R₂₆        is (C₁-C₄) alkyl or halogen.    -   (13) In one embodiment, R₂₁, R₂₂, and R₂₅ are each as defined,        where applicable, in any one of (1)-(11), and at least one R₂₆        is (C₁-C₂) alkyl or halogen.    -   (14) In one embodiment, R₂₁, R₂₂, and R₂₅ are each as defined,        where applicable, in any one of (1)-(11), and at least one R₂₆        is methyl or Cl.

R₂₁, R₂₂, R₂₅, and R₂₆ can each be selected from any of the groups andcombined as described above in Formula TL-V or TL-Va.

In another embodiment, a Targeting Ligand is a compound of FormulaTL-VI:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

B₆ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, wherein the aryl or heteroarylare optionally substituted with one to three R₃₁;

B₇ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, wherein the aryl or heteroarylare optionally substituted with one to three R₃₂;

X₄ is O or NR₃₃;

R₂₇ and R₂₈ are each independently H, (C₁-C₄) alkyl, or (C₁-C₄)haloalkyl;

each R₂₉ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

each R₃₀ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, or C(O)(C₁-C₄) alkyl;

each R₃₁ and each R₃₂ are independently (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

R₃₃ is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

s3 and s4 are each independently 0, 1, 2, or 3; and

s5 is 1 or 2;

wherein the Targeting Ligand is bonded to the Linker via the

next to

In some embodiments, B₆ is (C₆-C₁₀) aryl optionally substituted with oneto three R₃₁. In some embodiments, B₆ is (C₆-C₁₀) aryl substituted withone to three R₃₁. In other embodiments, B₆ is 5- or 6-memberedheteroaryl comprising 1-3 heteroatoms selected from N, S, and O,optionally substituted with one to three R₃₁. In other embodiments, B₆is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected fromN, S, and O, substituted with one to three R₃₁. In other embodiments, B₆is 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, S,and O, optionally substituted with one to three R₃₁. In otherembodiments, B₆ is 5-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, substituted with one to three R₃₁. In otherembodiments, B₆ is 6-membered heteroaryl comprising 1-3 heteroatomsselected from N, S, and O, optionally substituted with one to three R₃₁.In other embodiments, B₆ is 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, substituted with one to threeR₃₁. In other embodiments, B₆ is phenyl substituted with one to threeR₃₁. In other embodiments, B₆ is phenyl optionally substituted with oneto three R₃₁. In other embodiments, B₆ is phenyl.

In some embodiments, B₇ is (C₆-C₁₀) aryl optionally substituted with oneto three R₃₂. In some embodiments, B₇ is (C₆-C₁₀) aryl substituted withone to three R₃₂. In other embodiments, B₇ is phenyl optionallysubstituted with one to three R₃₂. In other embodiments, B₇ is phenylsubstituted with one to three R₃₂. In other embodiments, B₇ is phenyl.In other embodiments, B₇ is 5- or 6-membered heteroaryl comprising 1-3heteroatoms selected from N, S, and O, optionally substituted with oneto three R₃₂. In other embodiments, B₇ is 5- or 6-membered heteroarylcomprising 1-3 heteroatoms selected from N, S, and O, substituted withone to three R₃₂. In other embodiments, B₇ is 6-membered heteroarylcomprising 1-3 heteroatoms selected from N, S, and O, optionallysubstituted with one to three R₃₂. In other embodiments, B₇ is6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, andO, substituted with one to three R₃₂. In other embodiments, B₇ is5-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, andO, optionally substituted with one to three R₃₂. In other embodiments,B₇ is 5-membered heteroaryl comprising 1-3 heteroatoms selected from N,S, and O, substituted with one to three R₃₂. In other embodiments, B₇ isisoxazolyl optionally substituted with one to three R₃₂. In otherembodiments, B₇ is isoxazolyl substituted with one to three R₃₂. Inother embodiments, B₇ is isoxazolyl substituted with one or two R₃₂.

In some embodiments, X₄ is O. In other embodiments, X₄ is NR₃₃.

In some embodiments, R₂₇ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₂₇ is (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In otherembodiments, R₂₇ is H or (C₁-C₃) alkyl. In other embodiments, R₂₇ is(C₁-C₃) alkyl. In other embodiments, R₂₇ is methyl, ethyl, n-propyl, ori-propyl. In other embodiments, R₂₇ is H.

In some embodiments, R₂₈ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₂₈ is (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In otherembodiments, R₂₈ is H or (C₁-C₃) alkyl. In other embodiments, R₂₈ is(C₁-C₃) alkyl. In other embodiments, R₂₈ is methyl, ethyl, n-propyl, ori-propyl. In other embodiments, R₂₈ is H.

In some embodiments, each R₂₉ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₂₉ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₂₉ is independently halogen, OH, or NH₂. In other embodiments,each R₂₉ is independently (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In otherembodiments, each R₂₉ is independently (C₁-C₃) alkoxy or (C₁-C₃)haloalkoxy. In other embodiments, each R₂₉ is independently (C₁-C₃)alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, each R₂₉ isindependently (C₁-C₃) alkyl or (C₁-C₃) alkoxy. In other embodiments,each R₂₉ is independently (C₁-C₃) haloalkyl or (C₁-C₃) haloalkoxy. Inother embodiments, each R₂₉ is independently halogen, (C₁-C₃) alkoxy or(C₁-C₃) haloalkoxy. In other embodiments, each R₂₉ is independently(C₁-C₃) alkyl or halogen.

In some embodiments, each R₃₀ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, or C(O)(C₁-C₃)alkyl. In other embodiments, each R₃₀ is independently (C₁-C₃) alkyl,(C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In otherembodiments, each R₃₀ is independently (C₁-C₃) alkyl or (C₁-C₃)haloalkyl. In other embodiments, each R₃₀ is independently (C₁-C₃)alkoxy or (C₁-C₃) haloalkoxy. In other embodiments, each R₃₀ isindependently halogen or C(O)(C₁-C₃) alkyl. In other embodiments, eachR₃₀ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, halogen, orC(O)(C₁-C₃) alkyl. In other embodiments, each R₃₀ is independently(C₁-C₃) alkyl, halogen, or C(O)(C₁-C₃) alkyl. In other embodiments, eachR₃₀ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or C(O)(C₁-C₃)alkyl.

In some embodiments, each R₃₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₃₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₃₁ is independently halogen, OH, or NH₂. In other embodiments,each R₃₁ is independently (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In otherembodiments, each R₃₁ is independently (C₁-C₃) alkoxy or (C₁-C₃)haloalkoxy. In other embodiments, each R₃₁ is independently (C₁-C₃)alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, each R₃₁ isindependently (C₁-C₃) alkyl or (C₁-C₃) alkoxy. In other embodiments,each R₃₁ is independently (C₁-C₃) haloalkyl or (C₁-C₃) haloalkoxy. Inother embodiments, each R₃₁ is independently halogen, (C₁-C₃) alkoxy or(C₁-C₃) haloalkoxy. In other embodiments, each R₃₁ is independently(C₁-C₃) alkyl or halogen.

In some embodiments, each R₃₂ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₃₂ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₃₂ is independently halogen, OH, or NH₂. In other embodiments,each R₃₂ is independently (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In otherembodiments, each R₃₂ is independently (C₁-C₃) alkoxy or (C₁-C₃)haloalkoxy. In other embodiments, each R₃₂ is independently (C₁-C₃)alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, each R₃₂ isindependently (C₁-C₃) alkyl or (C₁-C₃) alkoxy. In other embodiments,each R₃₂ is independently (C₁-C₃) haloalkyl or (C₁-C₃) haloalkoxy. Inother embodiments, each R₃₂ is independently halogen, (C₁-C₃) alkoxy or(C₁-C₃) haloalkoxy. In other embodiments, each R₃₂ is independently(C₁-C₃) alkyl or halogen. In other embodiments, each R₃₂ isindependently methyl, ethyl, n-propyl, i-propyl, F, C₁, Br, or I. Inother embodiments, each R₃₂ is independently methyl, ethyl, n-propyl, ori-propyl. In other embodiments, at least one R₃₂ is i-propyl.

In some embodiments, R₃₃ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₃₃ is (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In otherembodiments, R₃₃ is H or (C₁-C₃) alkyl. In other embodiments, R₃₃ is(C₁-C₃) alkyl. In other embodiments, R₃₃ is methyl, ethyl, n-propyl, ori-propyl. In other embodiments, R₃₃ is H.

In some embodiments, s3 is 0. In other embodiments, s3 is 1. In otherembodiments, s3 is 2. In other embodiments, s3 is 3. In otherembodiments, s3 is 0 or 1. In other embodiments, s3 is 1 or 2. In otherembodiments, s3 is 2 or 3. In other embodiments, s3 is 0, 1, or 2. Inother embodiments, s3 is 1, 2, or 3.

In some embodiments, s4 is 0. In other embodiments, s4 is 1. In otherembodiments, s4 is 2. In other embodiments, s4 is 3. In otherembodiments, s4 is 0 or 1. In other embodiments, s4 is 1 or 2. In otherembodiments, s4 is 2 or 3. In other embodiments, s4 is 0, 1, or 2. Inother embodiments, s4 is 1, 2, or 3.

In some embodiments, s5 is 1. In other embodiments, s5 is 2.

Any of the groups described herein for any of B₆, B₇, X₄, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, R₃₂, R₃₃, s3, s4, and s5 can be combined with any of thegroups described herein for one or more of the remainder of B₆, B₇, X₄,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, s3, s4, and s5, and may further becombined with any of the groups described herein for the Linker.

For a Targeting Ligand of Formula TL-VI:

-   -   (1) In one embodiment, R₂₇ is H and R₂₈ is H.    -   (2) In one embodiment, R₂₇ is methyl and R₂₈ is H.    -   (3) In one embodiment, R₂₇ is H and R₂₈ is methyl.    -   (4) In one embodiment, R₂₇ is methyl and R₂₈ is methyl.    -   (5) In one embodiment, R₂₇ is H and X₄ is O.    -   (6) In one embodiment, R₂₇ is methyl and X₄ is NR₃₃.    -   (7) In one embodiment, R₂₈ is H and X₄ is O.    -   (8) In one embodiment, R₂₈ is methyl and X₄ is NR₃₃.    -   (9) In one embodiment, R₂₇ is H, R₂₈ is H, and X₄ is O.    -   (10) In one embodiment, R₂₇ is H, R₂₈ is H, and X₄ is NR₃₃.    -   (11) In one embodiment, B₆ is (C₆-C₁₀) aryl optionally        substituted with one to three R₃₁ and X₄ is O.    -   (12) In one embodiment, B₆ is (C₆-C₁₀) aryl optionally        substituted with one to three R₃₁ and X₄ is NR₃₃.    -   (13) In one embodiment, B₆ is (C₆-C₁₀) aryl and X₄ is O.    -   (14) In one embodiment, B₆ is (C₆-C₁₀) aryl and X₄ is NR₃₃.    -   (15) In one embodiment, B₆ is phenyl optionally substituted with        one to three R₃₁ and X₄ is O.    -   (16) In one embodiment, B₆ is phenyl optionally substituted with        one to three R₃₁ and X₄ is NR₃₃.    -   (17) In one embodiment, B₆ is phenyl and X₄ is O.    -   (18) In one embodiment, B₆ is phenyl and X₄ is NR₃₃.    -   (19) In one embodiment, B₆ is (C₆-C₁₀) aryl optionally        substituted with one to three R₃₁ and B₇ is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₃₂.    -   (20) In one embodiment, B₆ is (C₆-C₁₀) aryl optionally        substituted with one to three R₃₁ and B₇ is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        substituted with one to three R₃₂.    -   (21) In one embodiment, B₆ is (C₆-C₁₀) aryl and B₇ is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₃₂.    -   (22) In one embodiment, B₆ is (C₆-C₁₀) aryl and B₇ is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        substituted with one to three R₃₂.    -   (23) In one embodiment, B₆ is phenyl optionally substituted with        one to three R₃₁ and B₇ is 5-membered heteroaryl comprising 1-3        heteroatoms selected from N, S, and O, optionally substituted        with one to three R₃₂.    -   (24) In one embodiment, B₆ is phenyl optionally substituted with        one to three R₃₁ and B₇ is 5-membered heteroaryl comprising 1-3        heteroatoms selected from N, S, and O, substituted with one to        three R₃₂.    -   (25) In one embodiment, B₆ is phenyl and B₇ is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        optionally substituted with one to three R₃₂.    -   (26) In one embodiment, B₆ is phenyl and B₇ is 5-membered        heteroaryl comprising 1-3 heteroatoms selected from N, S, and O,        substituted with one to three R₃₂.    -   (27) In one embodiment, B₆ is (C₆-C₁₀) aryl optionally        substituted with one to three R₃₁ and B₇ is isoxazolyl        optionally substituted with one to three R₃₂.    -   (28) In one embodiment, B₆ is (C₆-C₁₀) aryl optionally        substituted with one to three R₃₁ and B₇ is isoxazolyl        substituted with one to three R₃₂.    -   (29) In one embodiment, B₆ is (C₆-C₁₀) aryl and B₇ is isoxazolyl        optionally substituted with one to three R₃₂.    -   (30) In one embodiment, B₆ is (C₆-C₁₀) aryl and B₇ is isoxazolyl        substituted with one to three R₃₂.    -   (31) In one embodiment, B₆ is phenyl optionally substituted with        one to three R₃₁ and B₇ is isoxazolyl optionally substituted        with one to three R₃₂.    -   (32) In one embodiment, B₆ is phenyl optionally substituted with        one to three R₃₁ and B₇ is isoxazolyl substituted with one to        three R₃₂.    -   (33) In one embodiment, B₆ is phenyl and B₇ is isoxazolyl        optionally substituted with one to three R₃₂.    -   (34) In one embodiment, B₆ is phenyl and B₇ is isoxazolyl        substituted with one to three R₃₂.    -   (35) In one embodiment, R₂₇, R₂₈, and X₄ are each as defined,        where applicable, in any one of (1)-(10), and B₆ is (C₆-C₁₀)        aryl optionally substituted with one to three R₃₁.    -   (36) In one embodiment, R₂₇, R₂₈, and X₄ are each as defined,        where applicable, in any one of (1)-(10), and B₆ is (C₆-C₁₀)        aryl.    -   (37) In one embodiment, R₂₇, R₂₈, and X₄ are each as defined,        where applicable, in any one of (1)-(10), and B₆ is phenyl        optionally substituted with one to three R₃₁.    -   (38) In one embodiment, R₂₇, R₂₈, and X₄ are each as defined,        where applicable, in any one of (1)-(10), and B₆ is phenyl.    -   (39) In one embodiment, B₆, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(10) and (35)-(38),        and B₇ is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms        selected from N, S, and O, optionally substituted with one to        three R₃₂.    -   (40) In one embodiment, B₆, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(10) and (35)-(38),        and B₇ is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms        selected from N, S, and O, substituted with one to three R₃₂.    -   (41) In one embodiment, B₆, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(10) and (35)-(38),        and B₇ is 5-membered heteroaryl comprising 1-3 heteroatoms        selected from N, S, and O, optionally substituted with one to        three R₃₂.    -   (42) In one embodiment, B₆, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(10) and (35)-(38),        and B₇ is 5-membered heteroaryl comprising 1-3 heteroatoms        selected from N, S, and O, substituted with one to three R₃₂.    -   (43) In one embodiment, B₆, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(10) and (35)-(38),        and B₇ is isoxazolyl optionally substituted with one to three        R₃₂.    -   (44) In one embodiment, B₆, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(10) and (35)-(38),        and B₇ is isoxazolyl substituted with one to three R₃₂.    -   (45) In one embodiment, B₆, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(10) and (35)-(38),        and B₇ is isoxazolyl substituted with one to two R₃₂.    -   (46) In one embodiment, B₆ and B₇ are each as defined, where        applicable, in any one of (11)-(34), and R₂₇ is H.    -   (47) In one embodiment, B₆ and B₇ are each as defined, where        applicable, in any one of (11)-(34), and R₂₇ is methyl.    -   (48) In one embodiment, B₆, B₇, and R₂₇ are each as defined,        where applicable, in any one of (11)-(34) and (46)-(47), and R₂₈        is H.    -   (49) In one embodiment, B₆, B₇, and R₂₇ are each as defined,        where applicable, in any one of (11)-(34) and (46)-(47), and R₂₈        is methyl.    -   (50) In one embodiment, B₆, B₇, R₂₇, and R₂₈ are each as        defined, where applicable, in any one of (11)-(34) and        (46)-(49), and X₄ is O.    -   (51) In one embodiment, B₆, B₇, R₂₇, and R₂₈ are each as        defined, where applicable, in any one of (11)-(34) and        (46)-(49), and X₄ is NR₃₃.    -   (52) In one embodiment, B₆, B₇, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(51), and s3 is 0.    -   (53) In one embodiment, B₆, B₇, R₂₇, R₂₈, and X₄ are each as        defined, where applicable, in any one of (1)-(51), and s3 is 1.    -   (54) In one embodiment, B₆, B₇, R₂₇, R₂₈, X₄, and s3 are each as        defined, where applicable, in any one of (1)-(53), and s4 is 0.    -   (55) In one embodiment, B₆, B₇, R₂₇, R₂₈, X₄, and s3 are each as        defined, where applicable, in any one of (1)-(53), and s4 is 1.    -   (56) In one embodiment, B₆, B₇, R₂₇, R₂₈, X₄, s3, and s4 are        each as defined, where applicable, in any one of (1)-(55), and        s5 is 0.    -   (57) In one embodiment, B₆, B₇, R₂₇, R₂₈, X₄, s3, and s4 are        each as defined, where applicable, in any one of (1)-(55), and        s5 is 1.    -   (58) In one embodiment, B₆, B₇, R₂₇, R₂₈, X₄, s3, s4, and s5 are        each as defined, where applicable, in any one of (1)-(57), and        R₃₂ is (C₁-C₄) alkyl.    -   (59) In one embodiment, B₆, B₇, R₂₇, R₂₈, X₄, s3, s4, and s5 are        each as defined, where applicable, in any one of (1)-(57), and        R₃₂ is (C₁-C₃) alkyl.    -   (60) In one embodiment, B₆, B₇, R₂₇, R₂₈, X₄, s3, s4, and s5 are        each as defined, where applicable, in any one of (1)-(57), and        R₃₂ is isopropyl.

In one embodiment, the compound of Formula TL-VI is of Formula TL-VIa:

wherein R₂₇, R₂₈, R₂₉, R₃₁, R₃₂, and s3 are each as defined above inFormula TL-VI.

For a Targeting Ligand of Formula TL-VIa:

-   -   (1) In one embodiment, R₂₇ is H and R₂₈ is H.    -   (2) In one embodiment, R₂₇ is methyl and R₂₈ is H.    -   (3) In one embodiment, R₂₇ is H and R₂₈ is methyl.    -   (4) In one embodiment, R₂₇ is methyl and R₂₈ is methyl.    -   (5) In one embodiment, R₂₇ and R₂₈ are each as defined, where        applicable, in any one of (1)-(4), and s3 is 0.    -   (6) In one embodiment, R₂₇ and R₂₈ are each as defined, where        applicable, in any one of (1)-(4) and s3 is 1.    -   (7) In one embodiment, R₂₇, R₂₈, and s3 are each as defined,        where applicable, in any one of (1)-(6), and R₃₂ is (C₁-C₄)        alkyl.    -   (8) In one embodiment, R₂₇, R₂₈, and s3 are each as defined,        where applicable, in any one of (1)-(6), and R₃₂ is (C₁-C₃)        alkyl.    -   (9) In one embodiment, R₂₇, R₂₈, and s3 are each as defined,        where applicable, in any one of (1)-(6), and R₃₂ is isopropyl.

R₂₇, R₂₈, R₃₂, and s3 can each be selected from any of the groups andcombined as described above in Formula TL-VI or TL-VIa.

Degron

The Degron serves to link a targeted protein, through a Linker and aTargeting Ligand, to a ubiquitin ligase for proteosomal degradation. Inone embodiment, the Degron is capable of binding to a ubiquitin ligase,such as an E3 ubiquitin ligase. In one embodiment, the Degron is capableof binding to cereblon.

In one embodiment, the Degron is of Formula D1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

Y is a bond, (CH₂)₁₋₆, (CH₂)₀₋₆—O, (CH₂)₀₋₆—C(O)NR₃₅, (CH₂)₀₋₆—NR₃₅C(O),(CH₂)₀₋₆—NH, or (CH₂)₀₋₆—NR₃₆;

Z₃ is C(O) or C(R₃₇)₂;

R₃₅ is H or C₁-C₆ alkyl;

R₃₆ is C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl;

each R₃₇ is independently H or C₁-C₃ alkyl;

each R₃₈ is independently C₁-C₃ alkyl;

R₃₉ is H, deuterium, C₁-C₃ alkyl, F, or C₁;

each R₄₀ is independently halogen, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy;

q is 0, 1, or 2; and

v is 0, 1, 2, or 3;

wherein the Degron is covalently bonded to the Linker via

In one embodiment, Z₃ is C(O).

In one embodiment, Z₃ is C(O) or CH₂.

In one embodiment, Z₃ is C(R₃₇)₂; and each R₃₇ is H. In one embodiment,Z₃ is C(R₃₇)₂; and one of R₃₇ is H, and the other is C₁-C₃ alkylselected from methyl, ethyl, and propyl. In one embodiment, Z₃ isC(R₃₇)₂; and each R₃₇ is independently selected from methyl, ethyl, andpropyl.

In one embodiment, Y is a bond.

In one embodiment, Y is a bond, O, or NH.

In one embodiment, Y is (CH₂)₁, (CH₂)₂, (CH₂)₃, (CH₂)₄, (CH₂)₅, or(CH₂)₆. In one embodiment, Y is (CH₂)₁, (CH₂)₂, or (CH₂)₃. In oneembodiment, Y is (CH₂)₁ or (CH₂)₂.

In one embodiment, Y is O, CH₂—O, (CH₂)₂—O, (CH₂)₃—O, (CH₂)₄—O,(CH₂)₅—O, or (CH₂)₆—O. In one embodiment, Y is O, CH₂—O, (CH₂)₂—O, or(CH₂)₃—O. In one embodiment, Y is O or CH₂—O. In one embodiment, Y is O.

In one embodiment, Y is C(O)NR₃₅, CH₂—C(O)NR₃₅, (CH₂)₂—C(O)NR₃₅,(CH₂)₃—C(O)NR₃₅, (CH₂)₄—C(O)NR₃₅, (CH₂)₅—C(O)NR₃₅, or (CH₂)₆—C(O)NR₃₅.In one embodiment, Y is C(O)R₃₅, CH₂—C(O)NR₃₅, (CH₂)₂—C(O)NR₃₅, or(CH₂)₃—C(O)NR₃₅. In one embodiment, Y is C(O)NR₃₅ or CH₂—C(O)NR₃₅. Inone embodiment, Y is C(O)NR₃₅.

In one embodiment, Y is NR₃₅C(O), CH₂—NR₃₅C(O), (CH₂)₂—NR₃₅C(O),(CH₂)₃—NR₃₅C(O), (CH₂)₄—NR₃₅C(O), (CH₂)₅—NR₃₅C(O), or (CH₂)₆—NR₃₅C(O).In one embodiment, Y is NR₃₅C(O), CH₂—NR₃₅C(O), (CH₂)₂—NR₃₅C(O), or(CH₂)₃—NR₃₅C(O). In one embodiment, Y is NR₃₅C(O) or CH₂—NR₃₅C(O). Inone embodiment, Y is NR₃₅C(O).

In one embodiment, R₃₅ is H. In one embodiment, R₃₅ is selected frommethyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl, andhexyl. In one embodiment, R₃₅ is C₁-C₃ alkyl selected from methyl,ethyl, and propyl.

In one embodiment, Y is NH, CH₂—NH, (CH₂)₂—NH, (CH₂)₃—NH, (CH₂)₄—NH,(CH₂)₅—NH, or (CH₂)₆—NH. In one embodiment, Y is NH, CH₂—NH, (CH₂)₂—NH,or (CH₂)₃—NH. In one embodiment, Y is NH or CH₂—NH. In one embodiment, Yis NH.

In one embodiment, Y is NR₃₆, CH₂—NR₃₆, (CH₂)₂—NR₃₆, (CH₂)₃—NR₃₆,(CH₂)₄—NR₃₆, (CH₂)₅—NR₃₆, or (CH₂)₆—NR₃₆. In one embodiment, Y is NR₃₆,CH₂—NR₃₆, (CH₂)₂—NR₃₆, or (CH₂)₃—NR₃₆. In one embodiment, Y is NR₃₆ orCH₂—NR₃₆. In one embodiment, Y is NR₃₆.

In one embodiment, R₃₆ is selected from methyl, ethyl, propyl, butyl,i-butyl, t-butyl, pentyl, i-pentyl, and hexyl. In one embodiment, R₃₆ isC₁-C₃ alkyl selected from methyl, ethyl, and propyl.

In one embodiment, R₃₆ is selected from C(O)-methyl, C(O)-ethyl,C(O)-propyl, C(O)-butyl, C(O)-i-butyl, C(O)-t-butyl, C(O)-pentyl,C(O)-i-pentyl, and C(O)-hexyl. In one embodiment, R₃₆ is C(O)—C₁-C₃alkyl selected from C(O)-methyl, C(O)-ethyl, and C(O)-propyl.

In one embodiment, R₃₇ is H.

In one embodiment, R₃₇ is C₁-C₃ alkyl selected from methyl, ethyl, andpropyl. In one embodiment, R₃₇ is methyl.

In one embodiment, q is 0.

In one embodiment, q is 1.

In one embodiment, q is 2.

In one embodiment, each R₃₈ is independently C₁-C₃ alkyl selected frommethyl, ethyl, and propyl.

In one embodiment, v is 0.

In one embodiment, v is 1.

In one embodiment, v is 2.

In one embodiment, v is 3.

In one embodiment, each R₄₀ is independently selected from halogen(e.g., F, C₁, Br, and I), OH, C₁-C₆ alkyl (e.g., methyl, ethyl, propyl,butyl, i-butyl, t-butyl, pentyl, i-pentyl, and hexyl), and C₁-C₆ alkoxy(e.g., methoxy, ethoxy, propoxy, butoxy, i-butoxy, t-butoxy, andpentoxy). In a further embodiment, each R₄₀ is independently selectedfrom F, C₁, OH, methyl, ethyl, propyl, butyl, i-butyl, t-butyl, methoxy,and ethoxy.

In one embodiment, R₃₉ is H, deuterium, or C₁-C₃ alkyl. In anotherembodiment, R₃₉ is H or C₁-C₃ alkyl. In a further embodiment, R₃₉ is inthe (S) or (R) configuration. In a further embodiment, R₃₉ is in the (S)configuration. In one embodiment, the compound comprises a racemicmixture of (S)—R₃₉ and (R)—R₃₉.

In one embodiment, R₃₉ is H.

In one embodiment, R₃₉ is deuterium.

In one embodiment, R₃₉ is C₁-C₃ alkyl selected from methyl, ethyl, andpropyl. In one embodiment, R₃₉ is methyl.

In one embodiment, R₃₉ is F or Cl. In a further embodiment, R₃₉ is inthe (S) or (R) configuration. In a further embodiment, R₃₉ is in the (R)configuration. In one embodiment, the compound comprises a racemicmixture of (S)—R₃₉ and (R)—R₃₉. In one embodiment, R₃₉ is F.

Any of the groups described herein for any of Y, Z₃, R₃₅, R₃₆, R₃₇, R₃₈,R₃₉, R₄₀, q and v can be combined with any of the groups describedherein for one or more of the remainder of Y, Z₃, R₃₅, R₃₆, R₃₇, R₃₈,R₃₉, R₄₀, q and v, and may further be combined with any of the groupsdescribed herein for the Linker.

For a Degron of Formula D1:

-   -   (1) In one embodiment, Z₃ is C(O) and Y is a bond.    -   (2) In one embodiment, Z₃ is C(O) and Y is NH.    -   (3) In one embodiment, Z₃ is C(O) and Y is (CH₂)₀₋₆—O. In a        further embodiment, Y is O.    -   (4) In one embodiment, Z₃ is C(O); Y is a bond; and q and v are        each 0.    -   (5) In one embodiment, Z₃ is C(O); Y is NH; and q and v are each        0.    -   (6) In one embodiment, Z₃ is C(O); Y is (CH₂)₀₋₆-0; and q and v        are each 0. In a further embodiment, Y is O.    -   (7) In one embodiment, Z₃ is C(O); Y is a bond; and R₃₇ is H.    -   (8) In one embodiment, Z₃ is C(O); Y is a bond; and R₃₇ is H.    -   (9) In one embodiment, Z₃ is C(O); Y is NH; and R₃₇ is H.    -   (10) In one embodiment, Z₃ is C(O); Y is NH; and R₃₉ is H.    -   (11) In one embodiment, Z₃ is C(O); Y is a bond; R₃₇ is H; and        R₃₉ is H.    -   (12) In one embodiment, Z₃ is C(O); Y is NH; R₃₇ is H; and R₃₉        is H.    -   (13) In one embodiment, Z₃ is C(O); Y is (CH₂)₀₋₆-0; and R₃₇        is H. In a further embodiment, Y is O.    -   (14) In one embodiment, Z₃ is C(O); Y is (CH₂)₀₋₆-0; and R₃₉        is H. In a further embodiment, Y is O.    -   (15) In one embodiment, Z₃ is C(O); Y is (CH₂)₀₋₆-0; R₃₇ is H;        and R₃₉ is H. In a further embodiment, Y is O.    -   (16) In one embodiment, q and v are each 0; and Y, Z₃, R₃₇, and        R₃₉ are each as defined in any of (1)-(3) and (7)-(15).    -   (17) In one embodiment, Z₃ is CH₂ and Y is a bond.    -   (18) In one embodiment, Z₃ is CH₂ and Y is NH.    -   (19) In one embodiment, Z₃ is CH₂ and Y is (CH₂)₀₋₆-0. In a        further embodiment, Y is O.    -   (20) In one embodiment, Z₃ is CH₂; Y is a bond; and q and v are        each 0.    -   (21) In one embodiment, Z₃ is CH₂; Y is NH; and q and v are each        0.    -   (22) In one embodiment, Z₃ is CH₂; Y is (CH₂)₀₋₆—O; and q and v        are each 0. In a further embodiment, Y is O.    -   (23) In one embodiment, Z₃ is CH₂; Y is a bond; and R₃₇ is H.    -   (24) In one embodiment, Z₃ is CH₂; Y is a bond; and R₃₉ is H.    -   (25) In one embodiment, Z₃ is CH₂; Y is NH; and R₃₇ is H.    -   (26) In one embodiment, Z₃ is CH₂; Y is NH; and R₃₉ is H.    -   (27) In one embodiment, Z₃ is CH₂; Y is a bond; R₃₇ is H; and        R₃₉ is H.    -   (28) In one embodiment, Z₃ is CH₂; Y is NH; R₃₇ is H; and R₃₉ is        H.    -   (29) In one embodiment, Z₃ is CH₂; Y is (CH₂)₀₋₆-0; and R₃₇        is H. In a further embodiment, Y is O.    -   (30) In one embodiment, Z₃ is CH₂; Y is (CH₂)₀₋₆-0; and R₃₉        is H. In a further embodiment, Y is O.    -   (31) In one embodiment, Z₃ is CH₂; Y is (CH₂)₀₋₆-0; R₃₇ is H;        and R₃₉ is H. In a further embodiment, Y is O.    -   (32) In one embodiment, q and v are each 0; and Y, Z₃, R₃₇, and        R₃₉ are each as defined in any of (17)-(19) and (23)-(31).

In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e,D1f, D1g, D1h, D1i, D1j, D1k, or D1;

or an enantiomer, diastereomer, or stereoisomer thereof, wherein Y, R₃₈,R₄₀, q, and v are each as defined above in Formula D1, and can beselected from any moieties or combinations thereof described above.

In one embodiment, Y is a bond, 0, or NH. In one embodiment, Y is abond. In one embodiment, Y is O. In one embodiment, Y is NH.

In one embodiment, the Degron is of Formula D2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

each R₄₁ is independently C₁-C₃ alkyl;

q′ is 0, 1, 2, 3 or 4; and

R₄₂ is H or C₁-C₃ alkyl, wherein the Degron is covalently bonded toanother moiety (e.g., a compound, or a Linker) via

In one embodiment, q′ is 0.

In one embodiment, q′ is 1.

In one embodiment, q′ is 2.

In one embodiment, q′ is 3.

In one embodiment, each R₄₁ is independently C₁-C₃ alkyl selected frommethyl, ethyl, and propyl.

In one embodiment, R₄₂ is methyl, ethyl, or propyl. In one embodiment,R₄₂ is methyl.

In one embodiment, the Degron is of Formula D2a:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

each R₄₁ is independently C₁-C₃ alkyl;

q′ is 0, 1, 2, 3 or 4; and

R₄₂ is H or C₁-C₃ alkyl, wherein the Degron is covalently bonded toanother moiety (e.g., a compound, or a Linker) via

In one embodiment, q′ is 0.

In one embodiment, q′ is 1.

In one embodiment, q′ is 2.

In one embodiment, q′ is 3.

In one embodiment, each R₄₁ is independently C₁-C₃ alkyl selected frommethyl, ethyl, and propyl.

In one embodiment, R₄₂ is methyl, ethyl, or propyl. In one embodiment,R₄₂ is methyl.

In one embodiment, the Degron is of Formula D2b:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

each R₄₁ is independently C₁-C₃ alkyl;

q′ is 0, 1, 2, 3 or 4; and

R₄₂ is H or C₁-C₃ alkyl, wherein the Degron is covalently bonded toanother moiety (e.g., a compound, or a Linker) via

In one embodiment, q′ is 0.

In one embodiment, q′ is 1.

In one embodiment, q′ is 2.

In one embodiment, q′ is 3.

In one embodiment, each R₄₁ is independently C₁-C₃ alkyl selected frommethyl, ethyl, and propyl.

In one embodiment, R₄₂ is methyl, ethyl, or propyl. In one embodiment,R₄₂ is methyl.

In one embodiment, the Degron is of Formula D2c:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

wherein the Degron is covalently bonded to another moiety (e.g., acompound, or a Linker) via

In one embodiment, the Degron is of Formula D2d:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

wherein the Degron is covalently bonded to another moiety (e.g., acompound, or a Linker) via

Linker

The Linker is a bond, a carbon chain, carbocyclic ring, or heterocyclicring that serves to link a Targeting Ligand with a Degron. In oneembodiment, the carbon chain optionally comprises one, two, three, ormore heteroatoms selected from N, O, and S. In one embodiment, thecarbon chain comprises only saturated chain carbon atoms. In oneembodiment, the carbon chain optionally comprises two or moreunsaturated chain carbon atoms (e.g., C═C or C≡C). In one embodiment,one or more chain carbon atoms in the carbon chain are optionallysubstituted with one or more substituents (e.g., oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₃ alkoxy, OH, halogen, NH₂, NH(C₁-C₃ alkyl),N(C₁-C₃ alkyl)₂, CN, C₃-C₈ cycloalkyl, heterocyclyl, phenyl, andheteroaryl).

In one embodiment, the Linker comprises at least 5 chain atoms (e.g., C,O, N, and S). In one embodiment, the Linker comprises less than 25 chainatoms (e.g., C, O, N, and S). In one embodiment, the Linker comprisesless than 20 chain atoms (e.g., C, O, N, and S). In one embodiment, theLinker comprises 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, or 24 chain atoms (e.g., C, O, N, and S). In oneembodiment, the Linker comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, or 24 chain atoms (e.g., C, O, N, andS). In one embodiment, the Linker comprises 5, 7, 9, 11, 13, 15, 17, or19 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linkercomprises 5, 7, 9, or 11 chain atoms (e.g., C, O, N, and S). In oneembodiment, the Linker comprises 11, 13, 15, 17, or 19 chain atoms(e.g., C, O, N, and S). In one embodiment, the Linker comprises 11, 13,15, 17, 19, 21, or 23 chain atoms (e.g., C, O, N, and S). In oneembodiment, the Linker comprises 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24chain atoms (e.g., C, O, N, and S). In one embodiment, the Linkercomprises 6, 8, 10, 12, 14, 16, 18, or 20 chain atoms (e.g., C, O, N,and S). In one embodiment, the Linker comprises 6, 8, 10, or 12 chainatoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises12, 14, 16, 18, or 20 chain atoms (e.g., C, O, N, and S).

In one embodiment, the Linker comprises from 11 to 19 chain atoms (e.g.,C, O, N, and S).

In one embodiment, the Linker is a carbon chain optionally substitutedwith non-bulky substituents (e.g., oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₃ alkoxy, OH, halogen, NH₂, NH(C₁-C₃ alkyl), N(C₁-C₃alkyl)₂, and CN). In one embodiment, the non-bulky substitution islocated on the chain carbon atom proximal to the Degron (e.g., thecarbon atom is separated from the carbon atom to which the Degron isbonded by at least 3, 4, or 5 chain atoms in the Linker). In oneembodiment, the non-bulky substitution is located on the chain carbonatom proximal to the Targeting Ligand (e.g., the carbon atom isseparated from the carbon atom to which the Degron is bonded by at least3, 4, or 5 chain atoms in the Linker).

In one embodiment, the Linker is of Formula L:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein

p1 is an integer selected from 0 to 12;

p2 is an integer selected from 0 to 12;

p3 is an integer selected from 1 to 6;

each W is independently absent, CH₂, O, S, or NR₃₄;

Z₁ is absent, C(O), CH₂, O, (CH₂)_(j)NR₃₄, O(CH₂)_(j)C(O)NR₃₄, C(O)NR₃₄,(CH₂)_(j)C(O)NR₃₄, NR₃₄C(O), (CH₂)_(j)NR₃₄C(O),C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄, C(O)(CH₂)_(j)C(O)NR₃₄,(CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄, or NR₃₄(CH₂)_(j)C(O)NR₃₄;

each R₃₄ is independently H or C₁-C₃ alkyl;

j is 1, 2, or 3;

k is 1, 2, or 3; and

Q1 is absent, C(O), NHC(O)(CH₂)₀₋₁, OCH₂C(O), O(CH₂)₁₋₂, or

wherein the Linker is covalently bonded to a Degron via the

next to Q₁, and covalently bonded to a Targeting Ligand via the

next to Z₁.

In one embodiment, the total number of chain atoms in the Linker is lessthan 30. In a further embodiment, the total number of chain atoms in theLinker is less than 20.

For a Linker of Formula L1:

-   -   (1) In one embodiment, p1 is an integer selected from 0 to 10.    -   (2) In one embodiment, p1 is an integer selected from 1 to 10.    -   (3) In one embodiment, p1 is selected from 1, 2, 3, 4, 5, and 6.    -   (4) In one embodiment, p1 is 0, 1, 3, or 5.    -   (5) In one embodiment, p1 is 0, 1, 2, or 3.    -   (6) In one embodiment, p1 is 0.    -   (7) In one embodiment, p1 is 1.    -   (8) In one embodiment, p1 is 2.    -   (9) In one embodiment, p1 is 3.    -   (10) In one embodiment, p1 is 4.    -   (11) In one embodiment, p1 is 5.    -   (12) In one embodiment, p2 is an integer selected from 0 to 10.    -   (13) In one embodiment, p2 is selected from 0, 1, 2, 3, 4, 5,        and 6.    -   (14) In one embodiment, p2 is 0, 1, 2, or 3.    -   (15) In one embodiment, p2 is 0.    -   (16) In one embodiment, p2 is 1.    -   (17) In one embodiment, p2 is 2.    -   (18) In one embodiment, p2 is 3.    -   (19) In one embodiment, p3 is an integer selected from 1 to 5.    -   (20) In one embodiment, p3 is 2, 3, 4, or 5.    -   (21) In one embodiment, p3 is 0, 1, 2, or 3.    -   (22) In one embodiment, p3 is 0.    -   (23) In one embodiment, p3 is 1.    -   (24) In one embodiment, p3 is 2.    -   (25) In one embodiment, p3 is 3.    -   (26) In one embodiment, p3 is 4.    -   (27) In one embodiment, at least one W is CH₂.    -   (28) In one embodiment, at least one W is O.    -   (29) In one embodiment, at least one W is S.    -   (30) In one embodiment, at least one W is NH.    -   (31) In one embodiment, at least one W is NR₃₄; and each R₃₄ is        independently C₁-C₃ alkyl selected from methyl, ethyl, and        propyl.    -   (32) In one embodiment, each W is O.    -   (33) In one embodiment, each W is CH₂.    -   (34) In one embodiment, j is 1, 2, or 3.    -   (35) In one embodiment, j is 1.    -   (36) In one embodiment, j is 2.    -   (37) In one embodiment, j is 3.    -   (38) In one embodiment, j is 2 or 3.    -   (39) In one embodiment, j is 1 or 2.    -   (40) In one embodiment, k is 1, 2, or 3.    -   (41) In one embodiment, k is 1.    -   (42) In one embodiment, k is 2.    -   (43) In one embodiment, k is 3.    -   (44) In one embodiment, k is 2 or 3.    -   (45) In one embodiment, k is 1 or 2.    -   (46) In one embodiment, Q₁ is absent.    -   (47) In one embodiment, Q₁ is NHC(O)CH₂.    -   (48) In one embodiment, Q₁ is O(CH₂)₁₋₂.    -   (49) In one embodiment, Q₁ is OCH₂.    -   (50) In one embodiment, Q₁ is OCH₂CH₂.    -   (51) In one embodiment, Q₁ is OCH₂C(O).    -   (52) In one embodiment, Q₁ is C(O).    -   (53) In one embodiment, Z₁ is absent.    -   (54) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₃₄; and R₃₄ is        C₁-C₃ alkyl selected from methyl, ethyl, and propyl.    -   (55) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₃₄; and R₃₄ is H.    -   (56) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₃₄; R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 1.    -   (57) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₃₄; R₃₄ is H; and        j is 1.    -   (58) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₃₄; R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 2.    -   (59) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₃₄; R₃₄ is H; and        j is 2.    -   (60) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₃₄; R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 3.    -   (61) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₃₄; and R₃₄ is H;        and j is 3.    -   (62) In one embodiment, Z₁ is C(O)NR₃₄; and R₃₄ is H.    -   (63) In one embodiment, Z₁ is C(O)NR₃₄; and R₃₄ is C₁-C₃ alkyl        selected from methyl, ethyl, and propyl.    -   (64) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₃₄; and R₃₄ is H.    -   (65) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₃₄; and R₃₄ is        C₁-C₃ alkyl selected from methyl, ethyl, and propyl.    -   (66) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₃₄; R₃₄ is H; and j        is 1.    -   (67) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₃₄; R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 1 (68)        In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₃₄; R₃₄ is H; and j is        2.    -   (69) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₃₄; R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 2.    -   (70) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₃₄; R₃₄ is H; and j        is 3.    -   (71) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₃₄; R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 3.    -   (72) In one embodiment, Z₁ is NR₃₄C(O); and R₃₄ is H.    -   (73) In one embodiment, Z₁ is NR₃₄C(O); and R₃₄ is C₁-C₃ alkyl        selected from methyl, ethyl, and propyl.    -   (74) In one embodiment, Z₁ is (CH₂)_(j)NR₃₄C(O); and R₃₄ is H.    -   (75) In one embodiment, Z₁ is (CH₂)_(j)NR₃₄C(O); and R₃₄ is        C₁-C₃ alkyl selected from methyl, ethyl, and propyl.    -   (76) In one embodiment, Z₁ is (CH₂)_(j)NR₃₄C(O); R₃₄ is H; and j        is 1.    -   (77) In one embodiment, Z₁ is (CH₂)_(j)NR₃₄C(O); R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 1 (78)        In one embodiment, Z₁ is (CH₂)_(j)NR₃₄C(O); R₃₄ is H; and j is        2.    -   (79) In one embodiment, Z₁ is (CH₂)_(j)NR₃₄C(O); R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 2.    -   (80) In one embodiment, Z₁ is (CH₂)_(j)NR₃₄C(O); R₃₄ is H; and j        is 3.    -   (81) In one embodiment, Z₁ is (CH₂)_(j)NR₃₄C(O); R₃₄ is C₁-C₃        alkyl selected from methyl, ethyl, and propyl; and j is 3.    -   (82) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        and each R₃₄ is independently H or C₁-C₃ alkyl selected from        methyl, ethyl, and propyl.    -   (83) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        and one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl. In one embodiment, Z₁ is        (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NH.    -   (84) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        each R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and j is 1.    -   (85) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        each R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and k is 1.    -   (86) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        each R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; j is 1; and k is 1.    -   (87) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl; and j is 1. In one embodiment, Z₁ is        (CH₂)_(k)NR₃₄(CH₂)C(O)NH.    -   (88) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl; and k is 1. In one embodiment, Z₁ is        (CH₂)NR₃₄(CH₂)_(j)C(O)NH.    -   (89) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl; j is 1; and k is 1. In one        embodiment, Z₁ is (CH₂)NR₃₄(CH₂)C(O)NH. In one embodiment, Z₁ is        (CH₂)N(CH₃)(CH₂)C(O)NH.    -   (90) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        each R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and j is 2.    -   (91) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        each R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and k is 2.    -   (92) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl; and j is 2. In one embodiment, Z₁ is        (CH₂)_(k)NR₃₄(CH₂)₂C(O)NH.    -   (93) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl; and k is 2. In one embodiment, Z₁ is        (CH₂)₂NR₃₄(CH₂)j C(O)NH.    -   (94) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        each R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and j is 3.    -   (95) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        each R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and k is 3.    -   (96) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl; and j is 3. In one embodiment, Z₁ is        (CH₂)_(k)NR₃₄(CH₂)₃C(O)NH.    -   (97) In one embodiment, Z₁ is (CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄;        one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl; and k is 3. In one embodiment, Z₁ is        (CH₂)₃NR₃₄(CH₂)j C(O)NH.    -   (98) In one embodiment, Z₁ is NR₃₄(CH₂)_(j)C(O)NR₃₄; and each        R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl.    -   (99) In one embodiment, Z₁ is NR₃₄(CH₂)_(j)C(O)NR₃₄; and each        R₃₄ is H.    -   (100) In one embodiment, Z₁ is NR₃₄(CH₂)_(j)C(O)NR₃₄; one of R₃₄        is H and one of R₃₄ is C₁-C₃ alkyl selected from methyl, ethyl,        and propyl; and j is 1.    -   (101) In one embodiment, Z₁ is NR₃₄(CH₂)_(j)C(O)NR₃₄; R₃₄ is H;        and j is 1.    -   (102) In one embodiment, Z₁ is NR₃₄(CH₂)_(j)C(O)NR₃₄; one of R₃₄        is H and one of R₃₄ is C₁-C₃ alkyl selected from methyl, ethyl,        and propyl; and j is 2.    -   (103) In one embodiment, Z₁ is NR₃₄(CH₂)_(j)C(O)NR₃₄; R₃₄ is H;        and j is 2.    -   (104) In one embodiment, Z₁ is NR₃₄(CH₂)_(j)C(O)NR₃₄; one of R₃₄        is H and one of R₃₄ is C₁-C₃ alkyl selected from methyl, ethyl,        and propyl; and j is 3.    -   (105) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; and        each R₃₄ is H.    -   (106) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; and        one of R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from        methyl, ethyl, and propyl.    -   (107) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; and        each R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl.    -   (108) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; each        R₃₄ is H; and j is 1.    -   (109) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; one of        R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and j is 1.    -   (110) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; each        R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and j is 1.    -   (111) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; each        R₃₄ is H; and j is 2.    -   (112) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; one of        R₃₄ is H; and one of R₃₄ is C₁-C₃ alkyl selected from methyl,        ethyl, and propyl, and j is 2.    -   (113) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; each        R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and j is 2.    -   (114) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; each        R₃₄ is H, and j is 3.    -   (115) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; one of        R₃₄ is H and one of R₃₄ is C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and j is 3.    -   (116) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄; each        R₃₄ is independently H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl; and j is 3.    -   (117) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; and R₃₄ is        H.    -   (118) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; and R₃₄ is        H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl.    -   (119) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; and R₃₄ is        C₁-C₃ alkyl selected from methyl, ethyl, and propyl.    -   (120) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is H;        and j is 1.    -   (121) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is H        or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is        1.    -   (122) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is        C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 1.    -   (123) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is H;        and j is 2.    -   (124) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is H        or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is        2.    -   (125) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is        C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 2.    -   (126) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is H;        and j is 3.    -   (127) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is H        or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is        3.    -   (128) In one embodiment, Z₁ is C(O)(CH₂)_(j)C(O)NR₃₄; R₃₄ is        C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 3.    -   (129) In one embodiment, Z₁ is C(O)NR₃₄ and p3 is 1.    -   (130) In one embodiment, Z₁ is C(O)NR₃₄ and p3 is 2.    -   (131) In one embodiment, Z₁ is C(O)NR₃₄ and p3 is 3.    -   (132) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 1, and p1 is 1-8.    -   (133) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 1, and p1 is 1.    -   (134) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 1, and p1 is 2.    -   (135) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 1, and p1 is 3.    -   (136) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 2, and p1 is 1-8.    -   (137) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 2, and p1 is 1.    -   (138) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 2, and p1 is 2.    -   (139) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 2, and p1 is 3.    -   (140) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 3, and p1 is 1-8.    -   (141) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 3, and p1 is 1.    -   (142) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 3, and p1 is 2.    -   (143) In one embodiment, Z₁ is C(O)NR₃₄, p3 is 3, and p1 is 2.    -   (144) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄ and p3 is        1.    -   (145) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄ and p3 is        2.    -   (146) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄ and p3 is        3.    -   (147) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄ and p3 is        1.    -   (148) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄ and p3 is        2.    -   (149) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄ and p3 is        3.    -   (150) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄ and p3 is        1.    -   (151) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄ and p3 is        2.    -   (152) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄ and p3 is        3.    -   (153) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 1,        and p1 is 1-8.    -   (154) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 1,        and p1 is 1.    -   (155) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 1,        and p1 is 2.    -   (156) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 1,        and p1 is 3.    -   (157) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 2,        and p1 is 1-8.    -   (158) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 2,        and p1 is 1.    -   (159) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 2,        and p1 is 2.    -   (160) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 2,        and p1 is 3.    -   (161) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 3,        and p1 is 1-8.    -   (162) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 3,        and p1 is 1.    -   (163) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 3,        and p1 is 2.    -   (164) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₁C(O)NR₃₄, p3 is 3,        and p1 is 3.    -   (165) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 1,        and p1 is 1-8.    -   (166) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 1,        and p1 is 1.    -   (167) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 1,        and p1 is 2.    -   (168) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 1,        and p1 is 3.    -   (169) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 2,        and p1 is 1-8.    -   (170) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 2,        and p1 is 1.    -   (171) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 2,        and p1 is 2.    -   (172) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 2,        and p1 is 3.    -   (173) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 3,        and p1 is 1-8.    -   (174) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 3,        and p1 is 1.    -   (175) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 3,        and p1 is 2.    -   (176) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₂C(O)NR₃₄, p3 is 3,        and p1 is 3.    -   (177) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 1,        and p1 is 1-8.    -   (178) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 1,        and p1 is 1.    -   (179) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 1,        and p1 is 2.    -   (180) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 1,        and p1 is 3.    -   (181) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 2,        and p1 is 1-8.    -   (182) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 2,        and p1 is 1.    -   (183) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 2,        and p1 is 2.    -   (184) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 2,        and p1 is 3.    -   (185) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 3,        and p1 is 1-8.    -   (186) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 3,        and p1 is 1.    -   (187) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 3,        and p1 is 2.    -   (188) In one embodiment, Z₁ is C(O)NR₃₄(CH₂)₃C(O)NR₃₄, p3 is 3,        and p1 is 3.    -   (189) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O) and p3 is 1.    -   (190) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O) and p3 is 2.    -   (191) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O) and p3 is 3.    -   (192) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O) and p3 is 1.    -   (193) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O) and p3 is 2.    -   (194) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O) and p3 is 3.    -   (195) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O) and p3 is 1.    -   (196) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O) and p3 is 2.    -   (197) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O) and p3 is 3.    -   (198) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 1, and p1        is 1-8.    -   (199) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 1, and p1        is 1.    -   (200) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 1, and p1        is 2.    -   (201) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 1, and p1        is 3.    -   (202) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 2, and p1        is 1-8.    -   (203) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 2, and p1        is 1.    -   (204) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 2, and p1        is 2.    -   (205) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 2, and p1        is 3.    -   (206) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 3, and p1        is 1-8.    -   (207) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 3, and p1        is 1.    -   (208) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 3, and p1        is 2.    -   (209) In one embodiment, Z₁ is (CH₂)₁NR₃₄C(O), p3 is 3, and p1        is 3.    -   (210) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 1, and p1        is 1-8.    -   (211) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 1, and p1        is 1.    -   (212) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 1, and p1        is 2.    -   (213) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 1, and p1        is 3.    -   (214) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 2, and p1        is 1-8.    -   (215) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 2, and p1        is 1.    -   (216) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 2, and p1        is 2.    -   (217) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 2, and p1        is 3.    -   (218) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 3, and p1        is 1-8.    -   (219) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 3, and p1        is 1.    -   (220) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 3, and p1        is 2.    -   (221) In one embodiment, Z₁ is (CH₂)₂NR₃₄C(O), p3 is 3, and p1        is 3.    -   (222) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 1, and p1        is 1-8.    -   (223) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 1, and p1        is 1.    -   (224) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 1, and p1        is 2.    -   (225) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 1, and p1        is 3.    -   (226) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 2, and p1        is 1-8.    -   (227) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 2, and p1        is 1.    -   (228) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 2, and p1        is 2.    -   (229) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 2, and p1        is 3.    -   (230) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 3, and p1        is 1-8.    -   (231) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 3, and p1        is 1.    -   (232) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 3, and p1        is 2.    -   (233) In one embodiment, Z₁ is (CH₂)₃NR₃₄C(O), p3 is 3, and p1        is 3.    -   (234) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄ and p3 is 1.    -   (235) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄ and p3 is 2.    -   (236) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄ and p3 is 3.    -   (237) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄ and p3 is 1.    -   (238) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄ and p3 is 2.    -   (239) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄ and p3 is 3.    -   (240) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄ and p3 is 1.    -   (241) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄ and p3 is 2.    -   (242) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄ and p3 is 3.    -   (243) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 1, and        p1 is 1-8.    -   (244) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 1, and        p1 is 1.    -   (245) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 1, and        p1 is 2.    -   (246) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 1, and        p1 is 3.    -   (247) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 2, and        p1 is 1-8.    -   (248) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 2, and        p1 is 1.    -   (249) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 2, and        p1 is 2.    -   (250) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 2, and        p1 is 3.    -   (251) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 3, and        p1 is 1-8.    -   (252) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 3, and        p1 is 1.    -   (253) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 3, and        p1 is 2.    -   (254) In one embodiment, Z₁ is C(O)(CH₂)₁C(O)NR₃₄, p3 is 3, and        p1 is 3.    -   (255) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 1, and        p1 is 1-8.    -   (256) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 1, and        p1 is 1.    -   (257) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 1, and        p1 is 2.    -   (258) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 1, and        p1 is 3.    -   (259) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 2, and        p1 is 1-8.    -   (260) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 2, and        p1 is 1.    -   (261) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 2, and        p1 is 2.    -   (262) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 2, and        p1 is 3.    -   (263) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 3, and        p1 is 1-8.    -   (264) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 3, and        p1 is 1.    -   (265) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 3, and        p1 is 2.    -   (266) In one embodiment, Z₁ is C(O)(CH₂)₂C(O)NR₃₄, p3 is 3, and        p1 is 3.    -   (267) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 1, and        p1 is 1-8.    -   (268) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 1, and        p1 is 1.    -   (269) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 1, and        p1 is 2.    -   (270) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 1, and        p1 is 3.    -   (271) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 2, and        p1 is 1-8.    -   (272) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 2, and        p1 is 1.    -   (273) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 2, and        p1 is 2.    -   (274) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 2, and        p1 is 3.    -   (275) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 3, and        p1 is 1-8.    -   (276) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 3, and        p1 is 1.    -   (277) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 3, and        p1 is 2.    -   (278) In one embodiment, Z₁ is C(O)(CH₂)₃C(O)NR₃₄, p3 is 3, and        p1 is 3.    -   (279) In one embodiment, p1, p3, and Z₁ are each as defined,        where applicable, in any one of (1)-(26) and (34)-(278), and W        is O.    -   (280) In one embodiment, p1, p3, and Z₁ are each as defined,        where applicable, in any one of (1)-(26) and (34)-(278), and W        is S.    -   (281) In one embodiment, p1, p3, and Z₁ are each as defined,        where applicable, in any one of (1)-(26) and (34)-(278), and W        is CH₂.    -   (282) In one embodiment, p1, p3, and Z₁ are each as defined,        where applicable, in any one of (1)-(26) and (34)-(278), and W        is NR₃₄.    -   (283) In one embodiment, p1, p3, W, and Z₁ are each as defined,        where applicable, in any one of (1)-(14) and (19)-(282), and p2        is 0.    -   (284) In one embodiment, p1, p3, W, and Z₁ are each as defined,        where applicable, in any one of (1)-(14) and (19)-(282), and p2        is 1.    -   (285) In one embodiment, p1, p3, W, and Z₁ are each as defined,        where applicable, in any one of (1)-(14) and (19)-(282), and p2        is 2.    -   (286) In one embodiment, p1, p3, W, and Z₁ are each as defined,        where applicable, in any one of (1)-(14) and (19)-(282), and p2        is 3.    -   (287) In one embodiment, p1, p2, p3, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(53) and        (129)-(286), and R₃₄ is H.    -   (288) In one embodiment, p1, p2, p3, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(53) and        (129)-(286), and R₃₄ is H or C₁-C₃ alkyl selected from methyl,        ethyl, and propyl.    -   (289) In one embodiment, p1, p2, p3, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(53) and        (129)-(286), and R₃₄ is C₁-C₃ alkyl selected from methyl, ethyl,        and propyl.    -   (290) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        absent.    -   (291) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        NHC(O)CH₂    -   (292) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        O(CH₂)₁₋₂.    -   (293) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        O(CH₂).    -   (294) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        O(CH₂CH₂).    -   (295) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        C(O).    -   (296) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        OCH₂C(O).    -   (297) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        NHC(O).    -   (298) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is        NHC(O)(CH₂).    -   (299) In one embodiment, p1, p2, p3, R₃₄, W, and Z₁ are each as        defined, where applicable, in any one of (1)-(289), and Q₁ is

In one embodiment, the Linker-Targeting Ligand (TL) has the structureselected from Table L:

TABLE L

(L1a)

(L1b)

(L1c)

(L1d)

(L1e)

(L1f)

(L1g)

(L1h)

(L1i)

(L1j)

(L1k)

(L1l)

(L1m)

(L1n)

(L1o)

(L1p)

(L1q)

(L1r)

(L1s)

(L1t)

(L1u)

(L1v)

(L1w)

(L1x)

(L1y)

(L1z)

(L1aa)

(L1bb)

(L1cc)

(L1dd)

(L1ee)

(L1ff)

(L1gg)wherein Z₁, W, Q₁, TL, p1, p2, and p3 are each as described above.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D1, and the Linker is selectedfrom L1a-L1gg. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1, and the Linkeris selected from L1a-L1c. In one embodiment, the Degron is of FormulaD1, and the Linker is selected from L1d-L1f. In one embodiment, theDegron is of Formula D1, and the Linker is selected from L1g-L1i. In oneembodiment, the Degron is of Formula D1, and the Linker is L1j-L1l. Inone embodiment, the Degron is of Formula D1, and the Linker is L1m-L1o.In one embodiment, the Degron is of Formula D1, and the Linker isL1p-L1r. In one embodiment, the Degron is of Formula D1, and the Linkeris L1s-L1u. In one embodiment, the Degron is of Formula D1, and theLinker is L1v-L1x. In one embodiment, the Degron is of Formula D1, andthe Linker is L1y-L1aa. In one embodiment, the Degron is of Formula D1,and the Linker is L1bb-L1dd. In one embodiment, the Degron is of FormulaD1, and the Linker is L1ee-L1gg.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f,D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected fromL1a-L1gg. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, Dig, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L1a-L1c. In one embodiment, the Degron is of Formula D1a, D1b, D1c,D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker isselected from L1d-L1f. In one embodiment, the Degron is of Formula D1a,D1b, Dic, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linkeris selected from L1g-L1i.

In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e,D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1j-L1l. In oneembodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,D1h, D1i, D1j, D1k, or D1l, and the Linker is L1m-L1o. In oneembodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,D1h, D1i, D1j, D1k, or D1l, and the Linker is L1p-L1r. In oneembodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,D1h, D1i, D1j, D1k, or D1l, and the Linker is L1s-L1u. In oneembodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,D1h, D1i, D1j, D1k, or D1l, and the Linker is L1v-L1x. In oneembodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,D1h, D1i, D1j, D1k, or D1l, and the Linker is L1y-L1aa. In oneembodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,D1h, D1i, D1j, D1k, or D1l, and the Linker is L1bb-L1dd. In oneembodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,D1h, D1i, D1j, D1k, or D1l, and the Linker is L1ee-L1gg.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2, and the Linker is selectedfrom L1a-L1gg. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D2, and the Linkeris selected from L1a-L1c. In one embodiment, the Degron is of FormulaD2, and the Linker is selected from L1d-L1f. In one embodiment, theDegron is of Formula D2, and the Linker is selected from L1g-L1i. In oneembodiment, the Degron is of Formula D2, and the Linker is L1j-L1l. Inone embodiment, the Degron is of Formula D2, and the Linker is L1m-L1o.In one embodiment, the Degron is of Formula D2, and the Linker isL1p-L1r. In one embodiment, the Degron is of Formula D2, and the Linkeris L1s-L1u. In one embodiment, the Degron is of Formula D2, and theLinker is L1v-L1x. In one embodiment, the Degron is of Formula D2, andthe Linker is L1y-L1aa. In one embodiment, the Degron is of Formula D2,and the Linker is L1bb-L1dd. In one embodiment, the Degron is of FormulaD2, and the Linker is L1ee-L1gg.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2a or D2b, and the Linker isselected from L1a-L1gg. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2aor D2b, and the Linker is selected from L1a-L1c. In one embodiment, theDegron is of Formula D2a or D2b, and the Linker is selected fromL1d-L1f. In one embodiment, the Degron is of Formula D2a or D2b, and theLinker is selected from L1g-L1i. In one embodiment, the Degron is ofFormula D2a or D2b, and the Linker is L1j-L1l. In one embodiment, theDegron is of Formula D2a or D2b, and the Linker is L1m-L1o. In oneembodiment, the Degron is of Formula D2a or D2b, and the Linker isL1p-L1r. In one embodiment, the Degron is of Formula D2a or D2b, and theLinker is L1s-L1u. In one embodiment, the Degron is of Formula D2a orD2b, and the Linker is L1v-L1x. In one embodiment, the Degron is ofFormula D2a or D2b, and the Linker is L1y-L1aa. In one embodiment, theDegron is of Formula D2a or D2b, and the Linker is L1bb-L1dd. In oneembodiment, the Degron is of Formula D2a or D2b, and the Linker isL1ee-L1gg.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2c or D2d, and the Linker isselected from L1a-L1gg. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2cor D2d, and the Linker is selected from L1a-L1c. In one embodiment, theDegron is of Formula D2c or D2d, and the Linker is selected fromL1d-L1f. In one embodiment, the Degron is of Formula D2c or D2d, and theLinker is selected from L1g-L1i. In one embodiment, the Degron is ofFormula D2c or D2d, and the Linker is L1j-L1l. In one embodiment, theDegron is of Formula D2c or D2d, and the Linker is L1m-L1o. In oneembodiment, the Degron is of Formula D2c or D2d, and the Linker isL1p-L1r. In one embodiment, the Degron is of Formula D2c or D2d, and theLinker is L1s-L1u. In one embodiment, the Degron is of Formula D2c orD2d, and the Linker is L1v-L1x. In one embodiment, the Degron is ofFormula D2c or D2d, and the Linker is L1y-L1aa. In one embodiment, theDegron is of Formula D2c or D2d, and the Linker is L1bb-L1dd. In oneembodiment, the Degron is of Formula D2c or D2d, and the Linker isL1ee-L1gg.

In one embodiment, the Linker is designed and optimized based on SAR(structure-activity relationship) and X-ray crystallography of theTargeting Ligand with regard to the location of attachment for theLinker.

In one embodiment, the optimal Linker length and composition vary by theTargeting Ligand and can be estimated based upon X-ray structure of theTargeting Ligand bound to its target. Linker length and composition canbe also modified to modulate metabolic stability and pharmacokinetic(PK) and pharmacodynamics (PD) parameters.

Some embodiments of present application relate to the bifunctionalcompounds having one of the following structures in Table A:

TABLE A Cmpd No. Structure I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

Some of the foregoing compounds can comprise one or more asymmetriccenters, and thus can exist in various isomeric forms, e.g.,stereoisomers and/or diastereomers. Accordingly, compounds of theapplication may be in the form of an individual enantiomer, diastereomeror geometric isomer, or may be in the form of a mixture ofstereoisomers. In one embodiment, the compounds of the application areenantiopure compounds. In another embodiment, mixtures of stereoisomersor diastereomers are provided.

Furthermore, certain compounds, as described herein, may have one ormore double bonds that can exist as either the Z or E isomer, unlessotherwise indicated. The application additionally encompasses thecompounds as individual Z/E isomers substantially free of other E/Zisomers and alternatively, as mixtures of various isomers.

In one embodiment, the present application relates to compounds thattarget proteins, such as protein kinases for degradation, which havenumerous advantages over inhibitors of protein function (e.g., proteinactivity) and can a) overcome resistance in certain cases; b) prolongthe kinetics of drug effect by destroying the protein, thus requiringresynthesis of the protein even after the compound has been metabolized;c) target all functions of a protein at once rather than a specificcatalytic activity or binding event; d) expand the number of drugtargets by including all proteins that a ligand can be developed for,rather than proteins whose activity (e.g., protein activity) can beaffected by a small molecule inhibitor, antagonist or agonist; and e)have increased potency compared to inhibitors due to the possibility ofthe small molecule acting catalytically.

Some embodiments of the present application relate to degradation orloss of 30% to 100% of the target protein. Some embodiments relate tothe loss of 50-100% of the target protein. Other embodiments relate tothe loss of 75-95% of the targeted protein.

A bifunctional compound of the present application (e.g., a bifunctionalcompound of any of the formulae described herein, or selected from anybifunctional compounds described herein) is capable of modulating (e.g.,decreasing) the amount of a targeted protein (e.g., a protein kinase). Abifunctional compound of the present application (e.g., a bifunctionalcompound of any of the formulae described herein, or selected from anybifunctional compounds described herein) is also capable of degrading atargeted protein (e.g., a protein kinase) through the UPP pathway.Accordingly, a bifunctional compound of the present application (e.g., abifunctional compound of any of the formulae described herein, orselected from any bifunctional compounds described herein) is capable oftreating or preventing a disease or disorder in which a protein kinaseplays a role. A bifunctional compound of the present application (e.g.,a bifunctional compound of any of the formulae described herein, orselected from any bifunctional compounds described herein) is alsocapable of treating or preventing a disease or disorder in which aprotein kinase plays a role or in which a protein kinase is deregulated(e.g., overexpressed).

Modulation of a protein kinase through UPP-mediated degradation by abifunctional compound of the application, such as those describedherein, provides a novel approach to the treatment, prevention, oramelioration of diseases or disorders in which a protein kinase plays arole including, but not limited to, cancer and metastasis, inflammation,arthritis, systemic lupus erthematosus, skin-related disorders,pulmonary disorders, cardiovascular disease, ischemia, neurodegenerativedisorders, liver disease, gastrointestinal disorders, viral andbacterial infections, central nervous system disorders, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, spinal cord injury, and peripheral neuropathy. Further,modulation of a protein kinase through UPP-mediated degradation by abifunctional compound of the application, such as those describedherein, also provides a new paradigm for treating, preventing, orameliorating diseases or disorders in which a protein kinase isderegulated.

In one embodiment, a bifunctional compound of the present application(e.g., a bifunctional compound of any of the formulae described herein,or selected from any bifunctional compounds described herein) is moreefficacious in treating a disease or condition (e.g., cancer) than, oris capable of treating a disease or condition resistant to, theTargeting Ligand, when the Targeting Ligand is administered alone (e.g.,not bonded to a Linker and a Degron). In one embodiment, a bifunctionalcompound of the present application (e.g., a bifunctional compound ofany of the formulae described herein, or selected from any bifunctionalcompounds described herein) is capable of modulating (e.g., decreasing)the amount of a protein kinase, and thus is useful in treating a diseaseor condition (e.g., cancer) in which a protein kinase plays a role.

In one embodiment, the bifunctional compound of the present applicationthat is more efficacious in treating a disease or condition than, or iscapable of treating a disease or condition resistant to, the TargetingLigand, when the Targeting Ligand is administered alone (e.g., notbonded to a Linker and a Degron), is more potent in inhibiting thegrowth of cells (e.g., cancer cells) or decreasing the viability ofcells (e.g., cancer cells), than the Targeting Ligand, when theTargeting Ligand is administered alone (e.g., not bonded to a Linker anda Degron). In one embodiment, the bifunctional compound inhibits thegrowth of cells (e.g., cancer cells) or decreases the viability of cells(e.g., cancer cells) at an IC₅₀ that is lower than the IC₅₀ of theTargeting Ligand (when the Targeting Ligand is administered alone (e.g.,not bonded to a Linker and a Degron)) for inhibiting the growth ordecreasing the viability of the cells. In one embodiment, the IC₅₀ ofthe bifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%,20%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%of the IC₅₀ of the Targeting Ligand. In one embodiment, the IC₅₀ of thebifunctional compound is at most 50%, 40%, 30%, 20%, 10%, 8%, 5%, 4%,3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC₅o of theTargeting Ligand. In one embodiment, the IC₅₀ of the bifunctionalcompound is at most 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%,0.4%, 0.3%, 0.2%, or 0.1% of the IC₅o of the Targeting Ligand. In oneembodiment, the IC₅₀ of the bifunctional compound is at most 10%, 8%,5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC₅₀ ofthe Targeting Ligand. In one embodiment, the IC₅₀ of the bifunctionalcompound is at most 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or0.1% of the IC₅₀ of the Targeting Ligand. In one embodiment, the IC₅₀ ofthe bifunctional compound is at most 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%,0.2%, or 0.1% of the IC₅₀ of the Targeting Ligand. In one embodiment,the IC₅₀ of the bifunctional compound is at most 1%, 0.8%, 0.5%, 0.4%,0.3%, 0.2%, or 0.1% of the IC₅₀ of the Targeting Ligand. In oneembodiment, the bifunctional compound inhibits the growth of cells(e.g., cancer cells) or decreases the viability of cells (e.g., cancercells) at an E_(max) that is lower than the E_(max) of the TargetingLigand (when the Targeting Ligand is administered alone (e.g., notbonded to a Linker and a Degron)) for inhibiting the growth ordecreasing the viability of the cells. In one embodiment, the E_(max) ofthe bifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%,20%, 10%, 8%, 5%, 4%, 3%, 2%, or 1% of the E_(max) of the TargetingLigand. In one embodiment, the E_(max) of the bifunctional compound isat most 50%, 40%, 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, or 1% of theE_(max) of the Targeting Ligand. In one embodiment, the E_(max) of thebifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,or 10% of the E_(max) of the Targeting Ligand.

In some embodiments, the inhibition of a protein kinase activity ismeasured by IC₅₀.

In some embodiments, the inhibition of a protein kinase activity ismeasured by EC₅₀.

Potency of the inhibitor can be determined by EC₅₀ value. A compoundwith a lower EC₅₀ value, as determined under substantially similarconditions, is a more potent inhibitor relative to a compound with ahigher EC₅₀ value. In some embodiments, the substantially similarconditions comprise determining protein kinase-dependent cellproliferation, in vitro or in vivo (e.g., in cells expressing a proteinkinase).

Potency of the inhibitor can also be determined by IC₅₀ value. Acompound with a lower IC₅₀ value, as determined under substantiallysimilar conditions, is a more potent inhibitor relative to a compoundwith a higher IC₅₀ value. In some embodiments, the substantially similarconditions comprise determining protein kinase-dependent cellproliferation, in vitro or in vivo (e.g., in cells expressing a proteinkinase).

In one embodiment, the bifunctional compounds of the present applicationare useful as anticancer agents, and thus may be useful in the treatmentof cancer, by effecting tumor cell death or inhibiting the growth oftumor cells. In certain exemplary embodiments, the disclosed anticanceragents are useful in the treatment of cancers and other proliferativedisorders, including, but not limited to breast cancer, cervical cancer,colon and rectal cancer, leukemia, lung cancer (e.g., non-small celllung cancer), melanoma, multiple myeloma, non-Hodgkin's lymphoma,ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer,leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblasticleukemias), malignant melanomas, and T-cell lymphoma.

A “selective protein kinase inhibitor,” can be identified, for example,by comparing the ability of a compound to inhibit one protein kinaseactivity to its ability to inhibit other kinases. For example, asubstance may be assayed for its ability to inhibit one protein kinaseactivity, as well as another protein kinase or other kinase. In someembodiments, the selectivity can be identified by measuring the EC₅₀ orIC₅₀ of the compounds.

The bifunctional compounds of the present disclosure can modulate and/orinhibit one of more kinases. In some embodiments, the bifunctionalcompounds of the present disclosure modulate and/or inhibit one proteinkinase. In other embodiment, the bifunctional compounds of the presentdisclosure modulate and/or inhibit more than one kinase. In someembodiments, the bifunctional compounds of the present disclosuremodulate and/or inhibit wild-type kinase. In other embodiments, thebifunctional compounds of the present disclosure modulate and/or inhibita mutant protein kinase. In other embodiments, the bifunctionalcompounds of the present disclosure modulate and/or inhibit both awild-type and mutant variant of a kinase.

In one aspect, the application provides a bifunctional compoundcomprising a protein kinase inhibitor (e.g., a protein tyrosine kinaseinhibitor or a serine-threonine kinase inhibitor), wherein thebifunctional compound is a more potent inhibitor of a drug-resistantprotein kinase mutant relative to a wild type protein kinase. Forexample, the compound can be at least about 2-fold, 3-fold, 5-fold,10-fold, 25-fold, 50-fold or about 100-fold more potent at inhibitingthe kinase activity of the drug-resistant protein kinase mutant relativeto the compound's inhibition of wild type protein kinase activity. Insome embodiments, the drug-resistant protein kinase mutant is resistantto Gleevec and other protein kinase inhibitor drugs. In someembodiments, the drug-resistant protein mutant comprises an activatingmutation. In another aspect, the application provides a compoundcomprising a protein kinase inhibitor, wherein the bifunctional compoundinhibits protein kinase activity of a drug-resistant protein kinasemutant harboring an activating mutation and a drug-resistance mutationwith less than a 10-fold difference in potency relative to a proteinkinase mutant harboring the activating mutation but not thedrug-resistance mutation. In some embodiments, the difference in potencyis less than about 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold,3-fold or 2-fold.

Definitions

Listed below are definitions of various terms used in this application.These definitions apply to the terms as they are used throughout thisspecification and claims, unless otherwise limited in specificinstances, either individually or as part of a larger group.

The term “alkyl,” as used herein, refers to saturated, straight orbranched-chain hydrocarbon radicals containing, in certain embodiments,between one and six carbon atoms. For example C₁-C₃ alkyl includesmethyl, ethyl, n-propyl, and isopropyl. Examples of C₁-C₆ alkyl radicalsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl, neopentyl, and n-hexyl radicals.

The term “alkoxy” refers to an —O-alkyl radical. For example C₁-C₃alkoxy includes methoxy, ethoxy, n-propoxy, and isopropoxy. Examples ofC₁-C₆ alkyl radicals include, but are not limited to, methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy, and n-hexoxyradicals.

The terms “hal,” “halo,” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “aryl,” as used herein, refers to a mono- or poly-cycliccarbocyclic ring system having one or more aromatic rings, fused ornon-fused, including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like.

The term “aralkyl,” as used herein, refers to an alkyl residue attachedto an aryl ring. Examples include, but are not limited to, benzyl,phenethyl and the like.

The term “cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or polycyclic saturated or partiallyunsaturated carbocyclic ring compound. Examples of C₃-C₈ cycloalkylinclude, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2]octyl. Also contemplated is a monovalent group derived from a monocyclicor polycyclic carbocyclic ring compound having at least onecarbon-carbon double bond by the removal of a single hydrogen atom.Examples of such groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

The term “heteroaryl,” as used herein, refers to a mono- or poly-cyclic(e.g., bi-, or tri-cyclic or more) fused or non-fused, radical or ringsystem having at least one aromatic ring, having from five to ten ringatoms of which one ring atoms is selected from S, O, and N; zero, one,or two ring atoms are additional heteroatoms independently selected fromS, O, and N; and the remaining ring atoms are carbon. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “heteroaralkyl,” as used herein, refers to an alkyl residueattached to a heteroaryl ring. Examples include, but are not limited to,pyridinylmethyl, pyrimidinylethyl and the like.

The term “heterocyclyl,” or “heterocycloalkyl,” as used herein, refersto a non-aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- ortri-cyclic group fused of non-fused system, where (i) each ring containsbetween one and three heteroatoms independently selected from oxygen,sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bondsand each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen andsulfur heteroatoms may optionally be oxidized, and (iv) the nitrogenheteroatom may optionally be quaternized. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl), e.g., —NH(C₁-C₆ alkyl), where C₁-C₁₂ alkyl is as previouslydefined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl)₂, e.g., —NH(C₁-C₆ alkyl), where C₁-C₁₂ alkyl is as previouslydefined.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

In accordance with the application, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

As described herein, compounds of the application may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the application. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. The terms “optionally substituted”, “optionally substitutedalkyl,” “optionally substituted “optionally substituted alkenyl,”“optionally substituted alkynyl”, “optionally substituted cycloalkyl,”“optionally substituted cycloalkenyl,” “optionally substituted aryl”,“optionally substituted heteroaryl,” “optionally substituted aralkyl”,“optionally substituted heteroaralkyl,” “optionally substitutedheterocycloalkyl,” and any other optionally substituted group as usedherein, refer to groups that are substituted or unsubstituted byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with substituents including, but not limited to:

—F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C3-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH— C₂-C₁₂-alkenyl, —OCONH— C₂-C₁₂-alkenyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂— heterocycloalkyl, NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, —NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NHheterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NHheterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

It is understood that the aryls, heteroaryls, alkyls, and the like canbe substituted.

The term “cancer” includes, but is not limited to, the followingcancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung:bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal, rectum; Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia (acute and chronic), acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

As used herein, “preventing” or “prevent” describes reducing oreliminating the onset of the symptoms or complications of the disease,condition or disorder.

The term “targeted protein(s)” is used interchangeably with “targetprotein(s)”, unless the context clearly dictates otherwise. In someembodiments, a “targeted protein” is a protein kinase.

In other embodiments, a targeted protein is one or more protein kinases.In other embodiments, the “targeted protein” is a protein tyrosinekinase. In other embodiments, the “targeted protein” is aserine-threonine kinase.

The terms “disease(s)”, “disorder(s)”, and “condition(s)” are usedinterchangeably, unless the context clearly dictates otherwise.

The term “therapeutically effective amount” of a bifunctional compoundor pharmaceutical composition of the application, as used herein, meansa sufficient amount of the bifunctional compound or pharmaceuticalcomposition so as to decrease the symptoms of a disorder in a subject.As is well understood in the medical arts a therapeutically effectiveamount of a bifunctional compound or pharmaceutical composition of thisapplication will be at a reasonable benefit/risk ratio applicable to anymedical treatment. It will be understood, however, that the total dailyusage of the compounds and compositions of the present application willbe decided by the attending physician within the scope of sound medicaljudgment. The specific inhibitory dose for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factors wellknown in the medical arts.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentapplication which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theapplication, or separately by reacting the free base or acid functionwith a suitable acid or base.

Examples of pharmaceutically acceptable salts include, but are notlimited to, nontoxic acid addition salts: salts formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid, or with organic acids such as aceticacid, maleic acid, tartaric acid, citric acid, succinic acid or malonicacid. Other pharmaceutically acceptable salts include, but are notlimited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the bifunctional compounds formed by the process of thepresent application which hydrolyze in vivo and include those that breakdown readily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein, refersto those prodrugs of the bifunctional compounds formed by the process ofthe present application which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals with undue toxicity, irritation, allergic response, andthe like, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use, as well as the zwitterionic forms,where possible, of the compounds of the present application. “Prodrug”,as used herein, means a compound which is convertible in vivo bymetabolic means (e.g., by hydrolysis) to afford any compound delineatedby the formulae of the instant application. Various forms of prodrugsare known in the art, for example, as discussed in Bundgaard, (ed.),Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods inEnzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al.,(ed). “Design and Application of Prodrugs, Textbook of Drug Design andDevelopment, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal ofDrug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of PharmaceuticalSciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs asNovel Drug Delivery Systems, American Chemical Society (1975); andBernard Testa & Joachim Mayer, “Hydrolysis In Drug And ProdrugMetabolism: Chemistry, Biochemistry And Enzymology,” John Wiley andSons, Ltd. (2002).

This application also encompasses pharmaceutical compositionscontaining, and methods of treating disorders through administering,pharmaceutically acceptable prodrugs of bifunctional compounds of theapplication. For example, compounds of the application having freeamino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of the application.The amino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

The application also provides for a pharmaceutical compositioncomprising a therapeutically effective amount of a bifunctional compoundof the application, or an enantiomer, diastereomer, stereoisomer, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In another aspect, the application provides a kit comprising abifunctional compound capable of inhibiting protein kinase activity ofat least one protein kinase selected from one or more compoundsdisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, optionally incombination with a second agent and instructions for use in treatingcancer. In one embodiment, the bifunctional compound in the kit inhibitsmore than one protein kinase In another aspect, the application providesa method of synthesizing a bifunctional compound disclosed herein.

The synthesis of the bifunctional compounds of the application can befound herein and in the Examples below.

Other embodiments are a method of making a bifunctional compound of anyof the formulae herein using any one, or combination of, reactionsdelineated herein. The method can include the use of one or moreintermediates or chemical reagents delineated herein.

Another aspect is an isotopically labeled bifunctional compound of anyof the formulae delineated herein. Such compounds have one or moreisotope atoms which may or may not be radioactive (e.g., ³H, ²H, ¹⁴C,¹³C, ¹⁸F, ³⁵S, ³²P, ¹²⁵I, and ¹³¹I) introduced into the bifunctionalcompound. Such compounds are useful for drug metabolism studies anddiagnostics, as well as therapeutic applications.

A bifunctional compound of the application can be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a bifunctional compound of the application can be prepared byreacting the free acid form of the bifunctional compound with apharmaceutically acceptable inorganic or organic base.

Alternatively, the salt forms of the bifunctional compounds of theapplication can be prepared using salts of the starting materials orintermediates.

The free acid or free base forms of the bifunctional compounds of theapplication can be prepared from the corresponding base addition salt oracid addition salt from, respectively. For example, a bifunctionalcompound of the application in an acid addition salt form can beconverted to the corresponding free base by treating with a suitablebase (e.g., ammonium hydroxide solution, sodium hydroxide, and thelike). A bifunctional compound of the application in a base additionsalt form can be converted to the corresponding free acid by treatingwith a suitable acid (e.g., hydrochloric acid, etc.).

Prodrugs of the bifunctional compounds of the application can beprepared by methods known to those of ordinary skill in the art (e.g.,for further details see Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriateprodrugs can be prepared by reacting a non-derivatized bifunctionalcompound of the application with a suitable carbamylating agent (e.g.,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike).

Protected derivatives of the bifunctional compounds of the applicationcan be made by means known to those of ordinary skill in the art. Adetailed description of techniques applicable to the creation ofprotecting groups and their removal can be found in T. W. Greene,“Protecting Groups in Organic Chemistry”, 3rd edition, John Wiley andSons, Inc., 1999.

Compounds of the present application can be conveniently prepared orformed during the process of the application, as solvates (e.g.,hydrates). Hydrates of bifunctional compounds of the present applicationcan be conveniently prepared by recrystallization from anaqueous/organic solvent mixture, using organic solvents such as dioxin,tetrahydrofuran or methanol.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Combinations of substituents and variables envisioned by thisapplication are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject).

When any variable (e.g., R₁₄) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more R₁₄moieties, then R₁₄ at each occurrence is selected independently from thedefinition of R₁₄. Also, combinations of substituents and/or variablesare permissible, but only if such combinations result in stablecompounds within a designated atom's normal valency.

In addition, some of the compounds of this application have one or moredouble bonds, or one or more asymmetric centers. Such compounds canoccur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double isomeric forms, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)-, or as(D)- or (L)- for amino acids. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers. The configuration of anycarbon-carbon double bond appearing herein is selected for convenienceonly and is not intended to designate a particular configuration unlessthe text so states; thus a carbon-carbon double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion. All such isomeric forms of such compounds areexpressly included in the present application.

Optical isomers may be prepared from their respective optically activeprecursors by the procedures described herein, or by resolving theracemic mixtures. The resolution can be carried out in the presence of aresolving agent, by chromatography or by repeated crystallization or bysome combination of these techniques which are known to those skilled inthe art. Further details regarding resolutions can be found in Jacques,et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons,1981).

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four non-identical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisapplication include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose. Common tautomeric pairs are:ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerismin heterocyclic rings (e.g., in nucleobases such as guanine, thymine andcytosine), amine-enamine and enamine-enamine. The compounds of thisapplication may also be represented in multiple tautomeric forms, insuch instances, the application expressly includes all tautomeric formsof the compounds described herein (e.g., alkylation of a ring system mayresult in alkylation at multiple sites, the application expresslyincludes all such reaction products).

In the present application, the structural formula of the bifunctionalcompound represents a certain isomer for convenience in some cases, butthe present application includes all isomers, such as geometricalisomers, optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In the present specification, the structuralformula of the compound represents a certain isomer for convenience insome cases, but the present application includes all isomers, such asgeometrical isomers, optical isomers based on an asymmetrical carbon,stereoisomers, tautomers, and the like.

Additionally, the compounds of the present application, for example, thesalts of the bifunctional compounds, can exist in either hydrated orunhydrated (the anhydrous) form or as solvates with other solventmolecules. Non-limiting examples of hydrates include monohydrates,dihydrates, etc. Non-limiting examples of solvates include ethanolsolvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

The synthesized bifunctional compounds can be separated from a reactionmixture and further purified by a method such as column chromatography,high pressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thebifunctional compounds of the formulae herein will be evident to thoseof ordinary skill in the art. Additionally, the various synthetic stepsmay be performed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent application. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this application may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The compounds of the application are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Method of Synthesizing the Compounds

Compounds of the present application can be prepared in a variety ofways using commercially available starting materials, compounds known inthe literature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentapplication. The processes generally provide the desired final compoundat or near the end of the overall process, although it may be desirablein certain instances to further convert the compound to apharmaceutically acceptable salt, ester or prodrug thereof. Suitablesynthetic routes are depicted in the schemes below.

Those skilled in the art will recognize if a stereocenter exists in thecompounds disclosed herein. Accordingly, the present applicationincludes both possible stereoisomers (unless specified in the synthesis)and includes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds of the present application can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present application can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below.

Compounds of the present application can be synthesized by following thesteps outlined in General Scheme 1, 2, and 3 which comprise differentsequences of assembling intermediates. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

wherein R₃₇, R₃₈, R₃₉, R₄₀, W, p1, q, and v are as defined herein above.

The general way of preparing representative compounds of the presentapplication (e.g., Compound of formula (I) shown above) usingintermediates 1a, 1b, 1c, 1d, 1e, 1f, and 1g is outlined in GeneralScheme 1. Reaction of 1a with 1b in the presence of potassium acetate(KOAc), an acid, e.g., acetic acid (AcOH), and optionally in a solvent,e.g., dimethylformamide (DMF), optionally at elevated temperatureprovides intermediate 1c. Reaction of 1d with fluoride 1c providesintermediate 1e. Deprotection of the 1e in the presence of TFA in asolvent, e.g., dichloromethane (DCM) or methanol (MeOH), provides 1f.Coupling of 1f and Target Ligand (TL) 1g under standard couplingconditions using a coupling reagent, e.g.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) andhydroxybenzotriazole, in a solvent, e.g., DCM or DMF, providesbifunctional compound of formula (I).

wherein R₃₇, R₃₈, R₃₉, R₄₀, W, p1, q, and v are as defined herein above.

The general way of preparing representative compounds of the presentapplication (e.g., Compound of formula (I) shown above) usingintermediates 1a, 1b, 1c, 1h, 1i, 1j, and 1k is outlined in GeneralScheme 2. Reaction of 1a with 1b in the presence of potassium acetate(KOAc), an acid, e.g., acetic acid (AcOH), and optionally in a solvent,e.g., dimethylformamide (DMF), optionally at elevated temperatureprovides intermediate 1c. Reaction of 1h with fluoride 1c providesintermediate 1i. Deprotection of the 1i in the presence of a strong acid(e.g., HCl) in a solvent, e.g., dioxane, provides 1j. Coupling of 1j andTarget Ligand (TL) 1k under standard coupling conditions using acoupling reagent, e.g.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU), and a base (e.g.,N,N-diisopropylethylamine (DIPEA)) in a solvent, e.g., DCM or DMF,provides bifunctional compound of formula (I).

The general way of preparing representative compounds of the presentapplication (e.g., Compound of formula (II) shown above) usingintermediates 3a, 3b, 3c, and 3d is outlined in General Scheme 3.Reaction of 3a with 3b in the presence of potassium iodide (KI), a base,e.g., potassium carbonate (K₂CO₃), and in a solvent, e.g., acetone),followed by Boc deprotection in the presence of strong acid (e.g.,hydrochloric acid (HCl) or trifluoroacetic acid (TFA)) in a solvent,e.g., dichloromethane (DCM) or methanol (MeOH) provides intermediate 3c.Coupling of amine 3d and Target Ligand 3c under standard couplingconditions using a coupling reagent, e.g.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) andhydroxybenzotriazole (HOBt), and a base (e.g., triethylamine (TEA)) in asolvent, e.g., DCM or DMF, provides bifunctional compound of formula(II) in shown in General Scheme 3.

Biological Assays Cell Viability Assay

Wild-type or cereblon null cells are treated with various concentrationsof a bifunctional compound of the application and allowed to grow. Cellsare then assayed to determine cell viability by measuring the amount ofATP present, which is an indicator of cell metabolic activity. Resultsare graphed as relative luminescent values.

Methods of the Application

In another aspect, the application provides a method of modulating akinase, comprising contacting the kinase with a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof, or with a pharmaceutical composition disclosed herein.In some embodiments, the kinase is a protein kinase. In someembodiments, the protein kinase is a protein tyrosine kinase. In otherembodiments, the protein kinase is a serine-threonine kinase.

In another aspect, the application provides a method of modulating atleast one kinase, comprising contacting the kinase with a bifunctionalcompound disclosed herein, or an enantiomer, diastereomer, orstereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof, or with a pharmaceutical compositiondisclosed herein. In some embodiments, the kinase is a protein kinase.In some embodiments, the protein kinase is a protein tyrosine kinase. Inother embodiments, the protein kinase is a serine-threonine kinase. Insome embodiments, the bifunctional compound modulates one proteinkinase. In other embodiments, the bifunctional compound modulates morethan one protein kinase.

In another aspect, the application provides a method of inhibiting akinase, comprising contacting the kinase with a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof, or with a pharmaceutical composition disclosed herein.In some embodiments, the kinase is a protein kinase. In someembodiments, the protein kinase is a protein tyrosine kinase. In otherembodiments, the protein kinase is a serine-threonine kinase.

In still another aspect, the application provides a method of inhibitinga protein kinase, the method comprising administering to a subject inneed thereof an effective amount of a bifunctional compound disclosedherein, or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.In some embodiments, the protein kinase is a protein tyrosine kinase. Inother embodiments, the protein kinase is a serine-threonine kinase. Insome embodiments, the bifunctional compound modulates one proteinkinase. In other embodiments, the bifunctional compound modulates morethan one protein kinase.

In still another aspect, the application provides a method of inhibitinga protein tyrosine kinase, the method comprising administering to asubject in need thereof an effective amount of a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof.

In another aspect, the application provides a method of inhibiting aserine-threonine kinase, the method comprising administering to asubject in need thereof an effective amount of a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof.

In still another aspect, the application provides a method of inhibitinga protein kinase, the method comprising administering to a subject inneed thereof an effective amount of a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier. In some embodiments, the protein kinase is a proteintyrosine kinase. In other embodiments, the protein kinase is aserine-threonine kinase.

In still another aspect, the application provides a method of inhibitinga protein tyrosine kinase, the method comprising administering to asubject in need thereof an effective amount of a pharmaceuticalcomposition comprising a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof and apharmaceutically acceptable carrier.

In still another aspect, the application provides a method of inhibitinga serine-threonine kinase, the method comprising administering to asubject in need thereof an effective amount of a pharmaceuticalcomposition comprising a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof and apharmaceutically acceptable carrier.

Another aspect of the application provides a method of treating orpreventing a disease, the method comprising administering to a subjectin need thereof an effective amount of a bifunctional compound disclosedherein, or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.In some embodiments, the disease is mediated by a kinase. In someembodiments, the kinase is a protein kinase. In other embodiments, thekinase is a protein tyrosine kinase. In other embodiments, the kinase isa serine-threonine kinase.

Another aspect of the application provides a method of treating orpreventing a disease, the method comprising administering to a subjectin need thereof an effective amount of a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier. In some embodiments, the disease is mediated by akinase. In some embodiments, the kinase is a protein kinase. In otherembodiments, the kinase is a protein tyrosine kinase. In otherembodiments, the kinase is a serine-threonine kinase.

In some embodiments, the disease is mediated by a protein tyrosinekinase (e.g., a protein tyrosine kinase plays a role in the initiationor development of the disease).

In some embodiments, the disease is mediated by a serine-threoninekinase (e.g., a serine-threonine kinase plays a role in the initiationor development of the disease).

In certain embodiments, the disease or disorder is cancer or aproliferation disease.

In further embodiments, the disease or disorder is lung cancer, coloncancer, breast cancer, prostate cancer, liver cancer, pancreas cancer,brain cancer, kidney cancer, ovarian cancer, stomach cancer, skincancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer,glioma, glioblastoma, hepatocellular carcinoma, papillary renalcarcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas,myelomas, or solid tumors.

In further embodiments, the disease or disorder is sarcoma. In furtherembodiments, the disease or disorder is sarcoma of the bones, muscles,tendons, cartilage, nerves, fat, or blood vessels. In furtherembodiments, the disease or disorder is soft tissue sarcoma, bonesarcoma, or osteosarcoma. In further embodiments, the disease ordisorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma,Karposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor,Synovial sarcoma, Pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma,reticulum cell sarcoma, meningiosarcoma, botryoid sarcoma,rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

In other embodiments, the disease or disorder is inflammation,arthritis, rheumatoid arthritis, spondyiarthropathies, gouty arthritis,osteoarthritis, juvenile arthritis, and other arthritic conditions,systemic lupus erthematosus (SLE), skin-related conditions, psoriasis,eczema, burns, dermatitis, neuroinflammation, allergy, pain, neuropathicpain, fever, pulmonary disorders, lung inflammation, adult respiratorydistress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronicpulmonary inflammatory disease, and chronic obstructive pulmonarydisease (COPD), cardiovascular disease, arteriosclerosis, myocardialinfarction (including post-myocardial infarction indications),thrombosis, congestive heart failure, cardiac reperfusion injury, aswell as complications associated with hypertension and/or heart failuresuch as vascular organ damage, restenosis, cardiomyopathy, strokeincluding ischemic and hemorrhagic stroke, reperfusion injury, renalreperfusion injury, ischemia including stroke and brain ischemia, andischemia resulting from cardiac/coronary bypass, neurodegenerativedisorders, liver disease and nephritis, gastrointestinal conditions,inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viraland bacterial infections, sepsis, septic shock, gram negative sepsis,malaria, meningitis, HIV infection, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, herpes virus, myalgias due to infection, influenza,autoimmune disease, graft vs. host reaction and allograft rejections,treatment of bone resorption diseases, osteoporosis, multiple sclerosis,cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bonecancer, epithelial call-derived neoplasia (epithelial carcinoma), basalcell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer,mouth cancer, esophageal cancer, small bowel cancer, stomach cancer,colon cancer, liver cancer, bladder cancer, pancreas cancer, ovariancancer, cervical cancer, lung cancer, breast cancer, skin cancer,squamous cell and/or basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that affect epithelial cellsthroughout the body, chronic myelogenous leukemia (CML), acute myeloidleukemia (AML) and acute promyelocytic leukemia (APL), angiogenesisincluding neoplasia, metastasis, central nervous system disorders,central nervous system disorders having an inflammatory or apoptoticcomponent, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis, spinal cord injury, andperipheral neuropathy, or B-Cell Lymphoma.

In further embodiments, the disease or disorder is inflammation,arthritis, rheumatoid arthritis, spondylarthropathies, gouty arthritis,osteoarthritis, juvenile arthritis, and other arthritic conditions,systemic lupus erthematosus (SLE), skin-related conditions, psoriasis,eczema, dermatitis, pain, pulmonary disorders, lung inflammation, adultrespiratory distress syndrome, pulmonary sarcoisosis, asthma, chronicpulmonary inflammatory disease, and chronic obstructive pulmonarydisease (COPD), cardiovascular disease, arteriosclerosis, myocardialinfarction (including post-myocardial infarction indications),congestive heart failure, cardiac reperfusion injury, inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome, leukemiaor lymphoma.

Another aspect of the application provides a method of treating a kinasemediated disorder, the method comprising administering to a subject inneed thereof an effective amount of a bifunctional compound disclosedherein, or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.In some embodiments, the bifunctional compound is an inhibitor of aprotein kinase. In other embodiments, the bifunctional compound is aninhibitor of a protein tyrosine kinase. In other embodiments, thebifunctional compound is an inhibitor of a serine-threonine kinase. Inother embodiments, the subject is administered an additional therapeuticagent. In other embodiments, the bifunctional compound and theadditional therapeutic agent are administered simultaneously orsequentially.

Another aspect of the application provides a method of treating a kinasemediated disorder, the method comprising administering to a subject inneed thereof an effective amount of a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier. In some embodiments, the bifunctional compound is aninhibitor of a protein kinase. In other embodiments, the bifunctionalcompound is an inhibitor of a protein tyrosine kinase. In otherembodiments, the bifunctional compound is an inhibitor of aserine-threonine kinase. In other embodiments, the subject isadministered an additional therapeutic agent. In other embodiments, thepharmaceutical composition comprising a bifunctional compound and theadditional therapeutic agent are administered simultaneously orsequentially.

In other embodiments, the disease or disorder is cancer. In furtherembodiments, the cancer is lung cancer, colon cancer, breast cancer,prostate cancer, liver cancer, pancreas cancer, brain cancer, kidneycancer, ovarian cancer, stomach cancer, skin cancer, bone cancer,gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma,hepatocellular carcinoma, papillary renal carcinoma, head and necksquamous cell carcinoma, leukemias, lymphomas, myelomas, or solidtumors.

Another aspect of the present application relates to a method oftreating or preventing a proliferative disease. The method comprisesadministering to a subject in need thereof an effective amount of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof.

Another aspect of the present application relates to a method oftreating or preventing a proliferative disease. The method comprisesadministering to a subject in need thereof an effective amount of apharmaceutical composition comprising a bifunctional compound disclosedherein, or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereofand a pharmaceutically acceptable carrier.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises activated proteinkinase, comprising administering to a subject in need thereof aneffective amount of a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof. In someembodiments, the cell comprises one activated protein kinase. In otherembodiments, the cell comprises more than one activated protein kinase.In other embodiments, the cell comprises an activated protein tyrosinekinase. In other embodiments, the cell comprises more than one activatedprotein tyrosine kinase. In other embodiments, the cell comprises anactivated serine-threonine kinase. In other embodiments, the cellcomprises more than one activated serine-threonine kinase.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises an activatedprotein tyrosine kinase, comprising administering to a subject in needthereof an effective amount of a bifunctional compound disclosed herein,or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises an activatedserine-threonine kinase, comprising administering to a subject in needthereof an effective amount of a bifunctional compound disclosed herein,or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises activated proteinkinase, comprising administering to a subject in need thereof aneffective amount of a pharmaceutical composition comprising abifunctional compound disclosed herein, or an enantiomer, diastereomer,or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof and a pharmaceutically acceptable carrier.In some embodiments, the cell comprises one activated protein kinase. Inother embodiments, the cell comprises more than one activated proteinkinase. In other embodiments, the cell comprises an activated proteintyrosine kinase. In other embodiments, the cell comprises more than oneactivated protein tyrosine kinase. In other embodiments, the cellcomprises an activated serine-threonine kinase. In other embodiments,the cell comprises more than one activated serine-threonine kinase.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises an activatedprotein tyrosine kinase, comprising administering to a subject in needthereof an effective amount of a pharmaceutical composition comprising abifunctional compound disclosed herein, or an enantiomer, diastereomer,or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof and a pharmaceutically acceptable carrier.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises an activatedserine-threonine kinase, comprising administering to a subject in needthereof an effective amount of a pharmaceutical composition comprising abifunctional compound disclosed herein, or an enantiomer, diastereomer,or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof and a pharmaceutically acceptable carrier.

In certain embodiments, the protein tyrosine kinase activation isselected from mutation of a protein tyrosine kinase, amplification of aprotein tyrosine kinase, expression of a protein tyrosine kinase, andligand mediated activation of a protein tyrosine kinase.

In certain embodiments, the serine-threonine kinase activation isselected from mutation of a serine-threonine kinase, amplification of aserine-threonine kinase, expression of a serine-threonine kinase, andligand mediated activation of a serine-threonine kinase.

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of inhibition of at least one protein kinase for thetreatment of cancer, comprising administering to the subject aneffective amount of a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof. In someembodiments, the protein kinase is a protein tyrosine kinase. In otherembodiments, the protein kinase is a serine-threonine kinase.

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of inhibition of a protein tyrosine kinase for thetreatment of cancer, comprising administering to the subject aneffective amount of a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof.

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of inhibition of a serine-threonine kinase for thetreatment of cancer, comprising administering to the subject aneffective amount of a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof.

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of inhibition of at least one protein kinase for thetreatment of cancer, comprising administering to the subject aneffective amount of a pharmaceutical composition comprising abifunctional compound disclosed herein, or an enantiomer, diastereomer,or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof. In some embodiments, the protein kinase isa protein tyrosine kinase. In other embodiments, the protein kinase is aserine-threonine kinase.

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of inhibition of a protein tyrosine kinase for thetreatment of cancer, comprising administering to the subject aneffective amount of a pharmaceutical composition comprising abifunctional compound disclosed herein, or an enantiomer, diastereomer,or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof and a pharmaceutically acceptable carrier.

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of inhibition of a serine-threonine kinase for thetreatment of cancer, comprising administering to the subject aneffective amount of a pharmaceutical composition comprising abifunctional compound disclosed herein, or an enantiomer, diastereomer,or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof and a pharmaceutically acceptable carrier.

In certain embodiments, the application provides a method of treatingany of the disorders described herein, wherein the subject is a human.In certain embodiments, the application provides a method of preventingany of the disorders described herein, wherein the subject is a human.

In another aspect, the application provides a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof, for use in the manufacture of a medicament for treatingor preventing a disease in which a protein kinase plays a role. In someembodiments, the protein kinase is a protein tyrosine kinase. In otherembodiments, the protein kinase is a serine-threonine kinase.

In still another aspect, the application provides a bifunctionalcompound disclosed herein, or an enantiomer, diastereomer, orstereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof, for use in the manufacture of a medicamentfor treating or preventing a disease in which a protein tyrosine kinaseplays a role.

In another aspect, the application provides a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof, for use in the manufacture of a medicament for treatingor preventing a disease in which a serine-threonine kinase plays a role.

In another aspect, the application provides a bifunctional compound ofthe application, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof for use in treating or preventing a disease in which aprotein kinase plays a role. In some embodiments, the protein kinase isa protein tyrosine kinase. In other embodiments, the protein kinase is aserine-threonine kinase.

In still another aspect, the application provides a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof for use in treating or preventing a diseasein which a protein tyrosine kinase plays a role.

In another aspect, the application provides a bifunctional compound ofthe application, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof for use in treating or preventing a disease in which aserine-threonine kinase plays a role.

In another aspect, the application provides a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier, for use in the manufacture of a medicament fortreating or preventing a disease in which a protein kinase plays a role.In some embodiments, the protein kinase is a protein tyrosine kinase. Inother embodiments, the protein kinase is a serine-threonine kinase.

In another aspect, the application provides a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier, for use in the manufacture of a medicament fortreating or preventing a disease in which a protein kinase plays a role.In some embodiments, the protein kinase is a protein tyrosine kinase. Inother embodiments, the protein kinase is a serine-threonine kinase.

In still another aspect, the application provides a pharmaceuticalcomposition comprising a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof and apharmaceutically acceptable carrier, for use in treating or preventing adisease in which protein tyrosine kinase plays a role.

In another aspect, the application provides a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier, for use in treating or preventing a disease in whichserine-threonine kinase plays a role.

In some embodiments, the bifunctional compounds of the application canmodulate and/or inhibit one or more protein kinases including, but notlimited to, Abl, Ack, AIE2, Akt, ALK, ALK2, ALK3, AIM1, ARK2, ARK1,AURA, Aurora-A, Aurora-B, Aurora-C, bcr-abl, Blk, BRAF, Brk, BTAK, Btk,c-fms, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7,CDK8, CDK9, CDK10, cRafl, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, Frk,Fes, Fps, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, fit-1, Fps, Frk, Fyn,Hck, IGF-1R, IRR, INS-R, Jak, KDR/FLK-1, Lck, Lyn, MEK, p38, PDGFR, PIK,PKC, PYK2, ros, Src, STK12, STK13, STK15, STK16, Syk, tie, tie2, TRK,VEGF, Yrk, and Zap70.

As inhibitors of protein kinases (e.g., protein tyrosine kinase,serine-threonine kinase, etc.), the bifunctional compounds andcompositions of this application are particularly useful for treating orlessening the severity of a disease, condition, or disorder where aprotein kinase is implicated in the disease, condition, or disorder. Inone aspect, the present application provides a method for treating orlessening the severity of a disease, condition, or disorder where aprotein kinase is implicated in the disease state. In another aspect,the present application provides a method for treating or lessening theseverity of a protein kinase mediated disease, condition, or disorderwhere inhibition of enzymatic activity is implicated in the treatment ofthe disease. In another aspect, this application provides a method fortreating or lessening the severity of a disease, condition, or disorderwith bifunctional compounds that inhibit enzymatic activity by bindingto the protein kinase. Another aspect provides a method for treating orlessening the severity of a protein kinase mediated disease, condition,or disorder by inhibiting enzymatic activity of the protein kinase witha protein kinase inhibitor.

In some embodiments, said method is used to treat or prevent a conditionselected from autoimmune diseases, inflammatory diseases, proliferativeand hyperproliferative diseases, immunologically-mediated diseases, bonediseases, metabolic diseases, neurological and neurodegenerativediseases, cardiovascular diseases, hormone related diseases, allergies,asthma, and Alzheimer's disease. In other embodiments, said condition isselected from a proliferative disorder and a neurodegenerative disorder.

One aspect of this application provides bifunctional compounds that areuseful for the treatment of diseases, disorders, and conditionscharacterized by excessive or abnormal cell proliferation. Such diseasesinclude, but are not limited to, a proliferative or hyperproliferativedisease, and a neurodegenerative disease. Examples of proliferative andhyperproliferative diseases include, without limitation, cancer. Theterm “cancer” includes, but is not limited to, the following cancers:breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus;larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma;lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma,lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas,adenocarcinoma; thyroid, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladdercarcinoma; liver carcinoma and biliary passages; kidney carcinoma;myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine;colonrectum, large intestine, rectum, brain and central nervous system;chronic myeloid leukemia (CML), and leukemia. The term “cancer”includes, but is not limited to, the following cancers: myeloma,lymphoma, or a cancer selected from gastric, renal, or and the followingcancers: head and neck, oropharangeal, non-small cell lung cancer(NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, andpulmonary.

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-celllymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia,chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodisplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian,testicular), lung cancer (e.g., small-cell and non-small cell), breastcancer, pancreatic cancer, melanoma and other skin cancers, stomachcancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer.

Additional exemplary forms of cancer which may be treated by the subjectbifunctional compounds include, but are not limited to, cancer ofskeletal or smooth muscle, stomach cancer, cancer of the smallintestine, rectum carcinoma, cancer of the salivary gland, endometrialcancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer,and pituitary cancer.

Additional cancers that the bifunctional compounds described herein maybe useful in preventing, treating and studying are, for example, coloncarcinoma, familiary adenomatous polyposis carcinoma and hereditarynon-polyposis colorectal cancer, or melanoma. Further, cancers include,but are not limited to, labial carcinoma, larynx carcinoma, hypopharynxcarcinoma, tongue carcinoma, salivary gland carcinoma, gastriccarcinoma, adenocarcinoma, thyroid cancer (medullary and papillarythyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervixcarcinoma, uterine corpus carcinoma, endometrium carcinoma, chorioncarcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumorssuch as glioblastoma, astrocytoma, meningioma, medulloblastoma andperipheral neuroectodermal tumors, gall bladder carcinoma, bronchialcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma, and plasmocytoma. In one aspect of the application, thepresent application provides for the use of one or more bifunctionalcompounds of the application in the manufacture of a medicament for thetreatment of cancer, including without limitation the various types ofcancer disclosed herein.

In some embodiments, the bifunctional compounds of this application areuseful for treating cancer, such as colorectal, thyroid, breast, andlung cancer; and myeloproliferative disorders, such as polycythemiavera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronicmyelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilicsyndrome, juvenile myelomonocytic leukemia, and systemic mast celldisease. In some embodiments, the bifunctional compounds of thisapplication are useful for treating hematopoietic disorders, inparticular, acute-myelogenous leukemia (AML), chronic-myelogenousleukemia (CML), acute-promyelocytic leukemia, and acute lymphocyticleukemia (ALL).

This application further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subjectbifunctional compounds may be administered for the purpose of preventingsaid hyperplasias, dysplasias or pre-cancerous lesions from continuingto expand or from becoming cancerous. Examples of pre-cancerous lesionsmay occur in skin, esophageal tissue, breast and cervicalintra-epithelial tissue.

Another aspect of this application provides a method for the treatmentor lessening the severity of a disease selected from a proliferative orhyperproliterative disease, or a neurodegenerative disease, comprisingadministering an effective amount of a bifunctional compound, or apharmaceutically acceptable composition comprising a bifunctionalcompound, to a subject in need thereof.

As inhibitors of a protein kinase (e.g., protein tyrosine kinase,serine-threonine kinase, etc.), the compounds and compositions of thisapplication are also useful in biological samples. One aspect of theapplication relates to inhibiting protein kinase activity in abiological sample, which method comprises contacting said biologicalsample with a bifunctional compound of the application or a compositioncomprising said bifunctional compound. The term “biological sample”, asused herein, means an in vitro or an ex vivo sample, including, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of protein kinase activity in a biological sample is usefulfor a variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, and biological specimen storage.

Another aspect of this application relates to the study of proteinkinases (e.g., protein tyrosine kinase, serine-threonine kinase, etc.)in biological and pathological phenomena; the study of intracellularsignal transduction pathways mediated by such protein kinases; and thecomparative evaluation of new protein kinase inhibitors. Examples ofsuch uses include, but are not limited to, biological assays such asenzyme assays and cell-based assays.

The activity of the compounds and compositions of the presentapplication as protein kinase (e.g., protein tyrosine kinase,serine-threonine, etc.) inhibitors may be assayed in vitro, in vivo, orin a cell line. In vitro assays include assays that determine inhibitionof either the enzyme activity or ATPase activity of the activatedkinase. Alternate in vitro assays quantitate the ability of theinhibitor to bind to the protein kinase and may be measured either byradio labelling the inhibitor prior to binding, isolating theinhibitor/protein kinase complex or inhibitor protein tyrosine kinasecomplex or serine-threonine kinase complex and determining the amount ofradio label bound, or by running a competition experiment where newinhibitors are incubated with the kinase bound to known radioligands.Detailed conditions for assaying a compound utilized in this applicationas an inhibitor of various kinases are set forth in the Examples below.

In accordance with the foregoing, the present application furtherprovides a method for preventing or treating any of the diseases ordisorders described above in a subject in need of such treatment, whichmethod comprises administering to said subject a therapeuticallyeffective amount of a bifunctional compound of the application, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof. For any of theabove uses, the required dosage will vary depending on the mode ofadministration, the particular condition to be treated and the effectdesired.

Pharmaceutical Compositions

In another aspect, the application provides a pharmaceutical compositioncomprising a therapeutically effective amount of a bifunctional compoundof the present application or an enantiomer, diastereomer, orstereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

Bifunctional compounds of the application can be administered aspharmaceutical compositions by any conventional route, in particularenterally, e.g., orally, e.g., in the form of tablets or capsules, orparenterally, e.g., in the form of injectable solutions or suspensions,or topically, e.g., in the form of lotions, gels, ointments or creams,or in a nasal or suppository form. Pharmaceutical compositionscomprising a compound of the present application in free form or in apharmaceutically acceptable salt form in association with at least onepharmaceutically acceptable carrier or diluent can be manufactured in aconventional manner by mixing, granulating or coating methods. Forexample, oral compositions can be tablets or gelatin capsules comprisingthe active ingredient together with a) diluents, e.g., lactose,dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)lubricants, e.g., silica, talcum, stearic acid, its magnesium or calciumsalt and/or polyethyleneglycol; for tablets also c) binders, e.g.,magnesium aluminum silicate, starch paste, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose and orpolyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar,alginic acid or its sodium salt, or effervescent mixtures; and/or e)absorbents, colorants, flavors and sweeteners. Injectable compositionscan be aqueous isotonic solutions or suspensions, and suppositories canbe prepared from fatty emulsions or suspensions. The compositions may besterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. In addition, they may also containother therapeutically valuable substances. Suitable formulations fortransdermal applications include an effective amount of a compound ofthe present application with a carrier. A carrier can include absorbablepharmacologically acceptable solvents to assist passage through the skinof the host. For example, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin. Matrix transdermal formulations may also beused. Suitable formulations for topical application, e.g., to the skinand eyes, are preferably aqueous solutions, ointments, creams or gelswell-known in the art. Such may contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives.

The pharmaceutical compositions of the present application comprise atherapeutically effective amount of a compound of the presentapplication formulated together with one or more pharmaceuticallyacceptable carriers. As used herein, the term “pharmaceuticallyacceptable carrier” means a non-toxic, inert solid, semi-solid or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes, polyethylenepolyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose andsucrose; starches such as corn starch and potato starch; cellulose andits derivatives such as sodium carboxymethyl cellulose, ethyl celluloseand cellulose acetate; powdered tragacanth; malt; gelatin; talc;excipients such as cocoa butter and suppository waxes, oils such aspeanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; cornoil and soybean oil; glycols such a propylene glycol or polyethyleneglycol; esters such as ethyl oleate and ethyl laurate, agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

The pharmaceutical compositions of this application can be administeredto humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous, oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisapplication with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents.

Dosage forms for topical or transdermal administration of a compound ofthis application include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches.

The active component is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, ear drops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this application.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this application, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisapplication, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Compounds and compositions of the application can be administered intherapeutically effective amounts in a combinational therapy with one ormore therapeutic agents (pharmaceutical combinations) or modalities,e.g., an anti-proliferative, anti-cancer, immunomodulatory oranti-inflammatory agent. Where the compounds of the application areadministered in conjunction with other therapies, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the condition beingtreated and so forth. Compounds and compositions of the application canbe administered in therapeutically effective amounts in a combinationaltherapy with one or more therapeutic agents (pharmaceuticalcombinations) or modalities, e.g., anti-proliferative, anti-cancer,immunomodulatory or anti-inflammatory agent, and/or non-drug therapies,etc. For example, synergistic effects can occur with anti-proliferative,anti-cancer, immunomodulatory or anti-inflammatory substances. Where thecompounds of the application are administered in conjunction with othertherapies, dosages of the co-administered compounds will of course varydepending on the type of co-drug employed, on the specific drugemployed, on the condition being treated and so forth.

Combination therapy includes the administration of the subject compoundsin further combination with one or more other biologically activeingredients (such as, but not limited to, a second protein tyrosinekinase inhibitor, a second serine-threonine kinase inhibitor, a secondand different antineoplastic agent, a kinase inhibitor and non-drugtherapies (such as, but not limited to, surgery or radiation treatment).For instance, the compounds of the application can be used incombination with other pharmaceutically active compounds, preferablycompounds that are able to enhance the effect of the compounds of theapplication. The compounds of the application can be administeredsimultaneously (as a single preparation or separate preparation) orsequentially to the other drug therapy or treatment modality. Ingeneral, a combination therapy envisions administration of two or moredrugs during a single cycle or course of therapy.

In another aspect of the application, the compounds may be administeredin combination with one or more separate pharmaceutical agents, e.g., achemotherapeutic agent, an immunotherapeutic agent, or an adjunctivetherapeutic agent.

EXAMPLES Analytical Methods, Materials, and Instrumentation

All reactions are monitored on a Waters Acquity UPLC/MS system (WatersPDA eX Detector, QDa Detector, Sample manager—FL, Binary SolventManager) using Acquity UPLC® BEH C18 column (2.1×50 mm, 1.7 m particlesize): solvent gradient=90% A at 0 min, 1% A at 1.8 min; solvent A=0.1%formic acid in Water; solvent B=0.1% formic acid in Acetonitrile; flowrate: 0.6 mL/min. Reaction products are purified by flash columnchromatography using CombiFlash® Rf with Teledyne Isco RediSep® Rf HighPerformance Gold or Silicycle SiliaSep™ High Performance columns (4 g,12 g, 24 g, 40 g, or 80 g), Waters HPLC system using SunFire™ Prep C18column (19×100 mm, 5 m particle size): solvent gradient=80% A at 0 min,5% A at 25 min; solvent A=0.035% TFA in Water; solvent B=0.035% TFA inMeOH; flow rate: 25 mL/min (Method A), and Waters Acquity UPLC/MS system(Waters PDA eλ Detector, QDa Detector, Sample manager—FL, Binary SolventManager) using Acquity UPLC® BEH C18 column (2.1×50 mm, 1.7 μm particlesize): solvent gradient=80% A at 0 min, 5% A at 2 min; solvent A=0.1%formic acid in Water; solvent B=0.1% formic acid in Acetonitrile; flowrate: 0.6 mL/min (method B). The purity of all compounds is over 95% andis analyzed with Waters LC/MS system. ¹H NMR is obtained using a 500 MHzBruker Avance III. Chemical shifts are reported relative to dimethylsulfoxide (δ=2.50) for ¹H NMR. Data are reported as (br=broad,s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet).

Abbreviations used in the following examples and elsewhere herein are:

-   -   AcOH acetic acid    -   br broad    -   DCM dichloromethane    -   DMAP 4-Dimethylaminopyridine    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   DIPEA N,N-Diisopropylethylamine    -   EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide    -   equiv equivalents    -   ESI electrospray ionization    -   EtOAc ethyl acetate    -   Et₃N triethylamine    -   Et₃SiH triethylsilane    -   HCl hydrochloric acid    -   h hour(s)    -   HATU        1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   HPLC high-performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   m multiplet    -   MeOH methanol    -   MHz megahertz    -   min minutes    -   MS mass spectrometry    -   NaBH(OAc)₃ Sodium triacetoxy borohydride    -   NMP N-methyl-2-pyrrolidone    -   NMR nuclear magnetic resonance    -   Pd(OAc)₂ palladium (II) acetate    -   ppm parts per million    -   t-BuOH tert-Butyl alcohol    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TsCl 4-Toluenesulfonyl chloride

Example 1: Synthesis of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (2-1)

To a solution of 3-fluorophthalic anhydride (2a, 200 mg, 1.20 mmol, 1equiv) in AcOH (4.0 mL, 0.3 M) was added 2,6-dioxopiperidin-3-aminehydrochloride (2b, 218 mg, 1.32 mmol, 1.1 equiv) and potassium acetate(366 mg, 3.73 mmol, 3.1 equiv). The reaction mixture was heated to 90°C. overnight and then diluted with water to 20 mL and cooled using anice bath for 30 min. The resulting slurry was transferred to a Falcontube, and centrifuged at 3500 rpm for 5 min. The supernatant wasdiscarded and the black solid was transferred to a 250 mL round-bottomedflask with methanol and concentrated in vacuo. The residue was purifiedby flash column chromatography on silica gel (eluting with 2% MeOH inCH₂Cl₂, R_(f)=0.3) to afford the title compound 2-1 as a white solid(288 mg, 86%). ¹H NMR (500 MHz, DMSO-d₆) δ 11.15 (s, 1H), 7.96 (ddd,J=8.3, 7.3, 4.5 Hz, 1H), 7.82-7.71 (m, 2H), 5.17 (dd, J=13.0, 5.4 Hz,1H), 2.90 (ddd, J=17.1, 13.9, 5.4 Hz, 1H), 2.65-2.47 (m, 2H), 2.10-2.04(m, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 173.2, 170.1, 166.5, 164.4, 157.3(d, J_(CF)=262.3 Hz), 138.5 (d, J_(CF)=7.9 Hz), 133.9, 123.5 (d,J_(CF)=19.6 Hz), 120.5 (d, J_(CF)=3.2 Hz), 117.5 (d, J_(CF)=12.4 Hz),49.6, 31.4, 22.3. MS (ESI) [M+H]⁺: 277.3.

Example 2: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione(3-1)

To a solution of 4-fluorophthalic anhydride (3a, 2.0 g, 12.0 mmol, 1equiv) in AcOH (40.0 mL, 0.3 M) was added 2,6-dioxopiperidin-3-aminehydrochloride (2b, 2.2 g, 13.2 mmol) and potassium acetate (3.66 g, 37.3mmol 3.1 equiv). The reaction mixture was heated to 90° C. overnight andthen diluted with water to 20 mL and cooled using an ice bath for 30min. The resulting slurry was transferred to a Falcon tube, andcentrifuged at 3500 rpm for 5 min. The supernatant was discarded and theblack solid was transferred to a 250 mL round-bottomed flask withmethanol and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (eluting with CH₂Cl₂:MeOH (15:1)) toafford the title compound 3-1 as a white solid (2.93 g, 88%) followingpurification by flash column chromatography on silica gel (CH₂Cl₂:MeOH(15:1)). ¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (s, 1H), 8.02 (dd, J=8.3, 4.5Hz, 1H), 7.86 (dd, J=7.4, 2.3 Hz, 1H), 7.77-7.68 (m, 1H), 5.17 (dd,J=13.0, 5.4 Hz, 1H), 2.90 (ddd, J=17.2, 13.9, 5.5 Hz, 1H), 2.66-2.52 (m,2H), 2.14-2.03 (m, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 172.7, 169.7,166.2, 166.0 (d, J_(CF)=254.5 Hz), 165.9 (d, J_(CF)=3.1 Hz), 134.2 (d,J_(CF)=10.2 Hz), 127.4 (d, J_(CF)=2.7 Hz), 126.3 (d, J_(CF)=9.8 Hz),121.7 (d, J_(CF)=23.8 Hz), 111.4 (d, J_(CF)=25.0 Hz), 49.2, 30.9, 21.9.MS (ESI) [M+H]⁺: 277.2.

Example 3: 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylicacid (4-1)

To a solution of 2,4-benzeetricarboxylic anhydride (4a, 200 mg, 1.04mmol, 1 equiv) in AcOH (4.0 mL, 0.3 M) was added3-aminopiperidine-2,6-dione hydrochloride (2b, 188 mg, 1.15 mmol, 1.1equiv) and potassium acetate (297 mg, 3.22 mmol, 3.1 equiv). Thereaction mixture was heated to 90° C. overnight and then diluted withwater to 20 mL and cooled using an ice bath for 30 min. The resultingslurry was transferred to a Falcon tube, and centrifuged at 3500 rpm for5 min. The supernatant was discarded and the black solid was transferredto a 250 mL round-bottomed flask with methanol and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (eluting with CH₂Cl₂:MeOH (9:1)) to afford the title compound 4-1 asa white solid (178 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (s, 1H),8.40 (dd, J=7.6, 1.4 Hz, 1H), 8.31 (d, J=1.4 Hz, 1H), 7.98 (d, J=7.7 Hz,1H), 5.18 (dd, J=12.8, 5.4 Hz, 1H), 2.90 (ddd, J=16.9, 13.8, 5.4 Hz,1H), 2.66-2.51 (m, 2H), 2.11-2.03 (m, 1H). MS (ESI) [M+H]⁺: 303.2.

Example 4: tert-butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)carbamate (5-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3-1, 100 mg,0.362 mmol, 1 equiv) in NMP (1.8 mL, 0.2 M) was added DIPEA (126 μL,0.724 mmol, 2 equiv) and N-boc-1,4-butanediamine (75 mg, 0.362 mmol, 1equiv). The reaction mixture was heated to 90° C. overnight and thencooled to room temperature. EtOAc (50 mL) was added. The organic layerwas washed with water (30 mL) and brine (3×30 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography on silica gel (eluting with 0 to 5% MeOHin CH₂Cl₂) to give the title compound 5-1 as a yellow solid (25 mg,16%). ¹H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 7.53 (d, J=8.3 Hz, 1H),6.90-6.85 (m, 1H), 6.68 (d, J=8.3 Hz, 1H), 4.92 (dd, J=12.0, 5.4 Hz,1H), 4.70 (s, 1H), 3.26-3.08 (m, 4H), 2.93-2.67 (m, 3H), 2.15-2.06 (m,1H), 1.72-1.52 (m, 4H), 1.44 (s, 9H). MS (ESI) [M+H]⁺: 445.3.

Example 5: tert-butyl(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)carbamate (6-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3-1, 100 mg,0.362 mmol, 1 equiv) in NMP (1.8 mL, 0.2 M) was added DIPEA (126 μL,0.724 mmol, 2 equiv) and N-boc-1,5-pentanediamine (81 mg, 0.362 mmol, 1equiv). The reaction mixture was heated to 90° C. overnight and thencooled to room temperature. EtOAc (50 mL) was added. The organic layerwas washed with water (30 mL) and brine (3×30 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (eluting with 0 to 5% MeOH inCH₂Cl₂) to give the title compound 6-1 as a yellow solid (39 mg, 23%).¹H NMR (500 MHz, CDCl₃) δ 8.41 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 6.90 (d,J=2.1 Hz, 1H), 6.70 (dd, J=8.4, 2.1 Hz, 1H), 4.95-4.82 (m, 2H),4.66-4.55 (m, 1H), 3.23-3.06 (m, 4H), 2.91-2.67 (m, 3H), 2.10 (ddd,J=10.5, 6.8, 3.3 Hz, 1H), 1.88-1.77 (m, 2H), 1.71-1.60 (m, 2H),1.56-1.48 (m, 2H), 1.43 (s, 9H). MS (ESI) [M+H]⁺: 459.3.

Example 6: tert-butyl(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)carbamate (7-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3-1, 700 mg,2.53 mmol, 1 equiv) in NMP (8.5 mL, 0.3 M) was added DIPEA (883 μL, 5.07mmol, 2 equiv) and N-boc-1,6-hexanediamine (568 μL, 2.53 mmol, 1 equiv).The reaction mixture was heated to 90° C. overnight and then cooled toroom temperature. EtOAc (50 mL) and satd. NaHCO₃(aq) (50 mL) were added.The aqueous phase was extracted with EtOAc (25 mL), and the combinedorganic layers were washed with water (2×30 mL) and brine (3×50 mL),dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (eluting with 0 to10% MeOH in CH₂Cl₂) to give the title compound 7-1 as a yellow solid(258 mg, 22%). ¹H NMR (500 MHz, CDCl₃) δ 8.01 (s, 1H), 7.61 (d, J=8.4Hz, 1H), 6.97 (d, J=2.1 Hz, 1H), 6.76 (dd, J=8.3, 2.2 Hz, 1H), 4.93 (dd,J=12.3, 5.3 Hz, 1H), 4.53 (s, 1H), 3.28-3.17 (m, 2H), 3.17-3.05 (m, 2H),2.91-2.69 (m, 3H), 2.17-2.07 (m, 1H), 1.74-1.57 (m, 2H), 1.56-1.47 (m,2H), 1.44 (s, 9H), 1.46-1.27 (m, 4H).

MS (ESI) [M+H]⁺: 473.2.

Example 7: tert-butyl(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamate (8-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3-1, 300 mg,1.09 mmol, 1 equiv) in NMP (5.4 mL, 0.2 M) was added DIPEA (378 μL, 2.17mmol, 2 equiv) and N-Boc-1,8-octanediamine (292 mg, 1.19 mmol, 1.1equiv). The reaction mixture was heated to 90° C. overnight and thencooled to room temperature. EtOAc (50 mL) and satd. NaHCO₃(aq) (50 mL)were added. The aqueous phase was extracted with EtOAc (25 mL), and thecombined organic layers were washed with water (2×30 mL) and brine (3×50mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (eluting with0 to 5% MeOH in CH₂Cl₂) to give the title compound 8-1 as a yellow solid(93 mg, 17%). ¹H NMR (500 MHz, CDCl₃) δ 8.46 (s, 1H), 7.56 (d, J=8.3 Hz,1H), 6.91 (d, J=2.1 Hz, 1H), 6.70 (dd, J=8.4, 2.2 Hz, 1H), 4.91 (dd,J=12.2, 5.3 Hz, 1H), 4.76 (s, 1H), 4.56 (s, 1H), 3.20-3.11 (m, 2H),3.13-3.00 (m, 2H), 2.91-2.64 (m, 3H), 2.13-2.04 (m, 1H), 1.62 (p, J=7.2Hz, 2H), 1.42 (s, 9H), 1.37-1.24 (m, 10H). MS (ESI) [M+H]⁺: 501.4.

Example 8: tert-butyl(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)-carbamate (9-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3-1, 100 mg,0.362 mmol, 1 equiv) in NMP (1.8 mL, 0.2 M) was added DIPEA (126 μL,0.724 mmol, 2 equiv) and tert-butyl (2-(2-aminoethoxy)ethyl)carbamate(74 mg, 0.362 mmol, 1 equiv). The reaction mixture was heated to 90° C.overnight and then cooled to room temperature. EtOAc (50 mL) was added.The organic layer was washed with water (30 mL) and brine (3×30 mL),dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (eluting with 0 to5% MeOH in CH₂Cl₂) to give the title compound 9-1 as a yellow solid (37mg, 22%). ¹H NMR (500 MHz, CDCl₃) δ 8.70 (s, 1H), 7.60-7.47 (m, 1H),6.99-6.85 (m, 1H), 6.74 (d, J=8.3 Hz, 1H), 5.06-4.96 (m, 1H), 4.92 (dd,J=12.0, 5.3 Hz, 1H), 3.72-3.63 (m, 2H), 3.58-3.48 (m, 2H), 3.33-3.24 (m,4H), 2.95-2.66 (m, 3H), 2.09 (ddd, J=10.5, 6.6, 3.2 Hz, 1H), 1.43 (s,9H). MS (ESI) [M+H]⁺: 461.2.

Example 9: tert-butyl(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl)carbamate (10-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3-1, 100 mg,0.362 mmol, 1 equiv) in NMP (1.8 mL, 0.2 M) was added DIPEA (126 μL,0.724 mmol, 2 equiv) and tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)-carbamate (99 mg, 0.362 mmol, 1equiv). The reaction mixture was heated to 90° C. overnight and thencooled to room temperature. EtOAc (50 mL) was added. The organic layerwas washed with water (30 mL) and brine (3×30 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (eluting with 0 to 5% MeOH inCH₂Cl₂) to give the title compound 10-1 as a yellow solid (25 mg, 14%).¹H NMR (500 MHz, CDCl₃) δ 8.52 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 6.95 (d,J=2.2 Hz, 1H), 6.76 (dd, J=8.5, 2.1 Hz, 1H), 5.14 (s, 1H), 5.02 (s, 1H),4.91 (dd, J=12.0, 5.4 Hz, 1H), 3.70 (h, J=5.9 Hz, 2H), 3.66-3.61 (m,4H), 3.58-3.52 (m, 2H), 3.43-3.37 (m, 2H), 3.34-3.28 (m, 2H), 2.90-2.66(m, 3H), 2.10 (ddd, J=10.2, 7.1, 3.4 Hz, 1H), 1.42 (d, J=4.2 Hz, 9H). MS(ESI) [M+H]⁺: 505.4.

Example 10: tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)benzoate (11-1)

A stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3-1, 200 mg,0.724 mmol, 1 equiv) in NMP (3.6 mL, 0.2 M) was added DIPEA (525 μL,1.45 mmol, 2 equiv) and tert-butyl 4-(aminomethyl)benzoate (165 mg,0.796 mmol, 1.1 equiv). The reaction mixture was heated to 90° C.overnight and then cooled to room temperature. EtOAc (50 mL) was added.The organic layer was washed with water (30 mL) and brine (3×30 mL),dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (eluting with 0 to5% MeOH in CH₂Cl₂) to give the title compound 11-1 as a yellow solid (57mg, 17%). MS (ESI) [M+H]⁺: 464.6.

Example 11: tert-butyl(8-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)benzamido)octyl)carbamate (12-1)

To a solution of tert-butyl(8-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)benz-amido)octyl)carbamate(11-1, 57 mg, 0.123 mmol, 1 equiv) was added (4M, dioxane, 300 μL). Thereaction mixture was stirred at room temperature for 1 h and thenconcentrated in vacuo. The resulting residue was taken up in DMF (1.2mL, 0.1 M) and N-boc-1,8-octanediamine (30 mg, 0.123 mmol, 1 equiv),HATU (47 mg, 0.123 mmol, 1 equiv) and DIPEA (86 μL, 0.492 mmol, 4 equiv)were added. The reaction mixture was stirred at room temperatureovernight and EtOAc (20 mL) was then added. The organic layer was washedwith satd. NaHCO₃(aq) (20 mL), water (20 mL) and brine (3×15 mL), driedover Na₂SO₄, filtered, and concentrated in vacuo. The resulting cruderesidue was purified by flash column chromatography on silica gel(eluting with 0 to 10% MeOH in CH₂Cl₂) to give the title compound 12-1as a yellow solid (40 mg, 51%). MS (ESI) [M+H]⁺: 634.5.

Example 12: tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzoate (13-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (2-1, 200 mg,0.724 mmol, 1 equiv) in NMP (3.6 mL, 0.2 M) was added DIPEA (525 μL,1.45 mmol, 2 equiv) and tert-butyl 4-(aminomethyl)benzoate (165 mg,0.796 mmol, 1.1 equiv). The reaction mixture was heated to 90° C.overnight and then cooled to room temperature. EtOAc (50 mL) was addedand the organic layer was washed with water (30 mL) and brine (3×30 mL),dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (eluting with 0 to5% MeOH in CH₂Cl₂) to give the title compound 13-1 as a yellow solid(165 mg, 50%). MS (ESI) [M+H]⁺: 464.7.

Example 13: tert-butyl(8-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzamido)octyl)carbamate (14-1)

To a solution of tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzoate(13-1, 165 mg, 0.363 mmol, 1 equiv) was added HCl (4M, dioxane, 300pjL). The reaction mixture was stirred at room temperature for 1 h andthen concentrated in vacuo. The resulting residue was taken up in DMF(3.6 mL, 0.1 M) and N-boc-1,8-octanediamine (89 mg, 0.363 mmol, 1equiv), HATU (138 mg, 0.363 mmol, 1 equiv) and DIPEA (253 μL, 1.45 mmol,4 equiv) were added. The reaction mixture was stirred at roomtemperature overnight and EtOAc (20 mL) was then added. The organiclayer was washed with satd. NaHCO₃(aq) (20 mL), water (20 mL) and brine(3×15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(eluting with 0 to 10% MeOH in CH₂Cl₂) to give the title compound 14-1as a yellow solid (158 mg, 69%). MS (ESI) [M+H]⁺: 634.5.

Example 14: tert-butyl(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamate (15-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (2-1, 100 mg,0.362 mmol, 1 equiv) in NMP (1.8 mL, 0.2 M) was added DIPEA (126 μL,0.724 mmol, 2 equiv) and N-boc-1,6-hexanediamine (86 mg, 0.398 mmol, 1.1equiv). The reaction mixture was heated to 90° C. overnight and thencooled to room temperature. EtOAc (50 mL) was added and the organiclayer was washed with water (50 mL) and brine (3×30 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (eluting with 0 to 5% MeOH inCH₂Cl₂) to give the title compound 15-1 as a yellow solid (95 mg, 56%).¹H NMR (500 MHz, CDCl₃) δ 8.25 (s, 1H), 7.53-7.46 (m, 1H), 7.08 (d,J=7.1 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.22 (s, 1H), 4.91 (dd, J=12.2,5.3 Hz, 1H), 4.53 (s, 1H), 3.25 (t, J=7.0 Hz, 2H), 3.10 (d, J=8.0 Hz,2H), 2.94-2.66 (m, 3H), 2.19-2.07 (m, 1H), 1.72-1.61 (m, 2H), 1.53-1.46(m, 2H), 1.43 (s, 9H), 1.36 (q, J=8.0 Hz, 4H). MS (ESI) [M+H]⁺: 473.4.

Example 15: tert-butyl(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate (16-1)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (2-1, 60 mg,0.217 mmol, 1 equiv) in NMP (1.1 mL, 0.2 M) was added DIPEA (76 μL,0.434 mmol, 2 equiv) and N-boc-1,8-octanediamine (58 mg, 0.239 mmol, 1.1equiv). The reaction mixture was heated to 90° C. overnight and thencooled to room temperature. EtOAc (30 mL) and satd. NaHCO₃(aq) (30 mL)were added and the aqueous phase was extracted with EtOAc (25 mL). Thecombined organic layers were washed with water (2×30 mL) and brine (3×50mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (eluting with5% MeOH in CH₂Cl₂) to give the title compound 16-1 as a yellow solid (93mg, 17%). ¹H NMR (500 MHz, CDCl₃) δ 8.30 (s, 1H), 7.48 (dd, J=8.5, 7.2Hz, 1H), 7.07 (d, J=7.1 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.29-6.19 (m,1H), 4.95-4.85 (m, 1H), 4.53 (s, 1H), 3.30-3.19 (m, 2H), 3.15-3.02 (m,2H), 2.92-2.66 (m, 3H), 2.16-2.07 (m, 1H), 1.64 (j, J=12.7, 8.2, 4.8 Hz,2H), 1.43 (s, 9H), 1.37-1.24 (m, 10H). MS (ESI) [M+H]⁺: 501.4.

Example 16: tert-butyl(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxamido)hexyl)carbamate (17-1)

To a solution of2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylic acid (4-1,20 mg, 0.0662 mmol, 1 equiv) in DMF (662 μL, 0.1 M) was addedN-boc-1,6-hexanediamine (14.3 mg, 0.0662 mmol, 1 equiv), HATU (25.2 mg,0.0662 mmol, 1 equiv) and DIPEA (23 μL, 0.132 mmol, 2 equiv). Thereaction mixture was stirred at room temperature overnight and thenEtOAc (20 mL) was added. The organic layer was washed with satd.NaHCO₃(aq) (20 mL), water (20 mL) and brine (3×15 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (eluting with 0 to 10% MeOH inCH₂Cl₂) to give the title compound 17-1 as a white solid (19 mg, 56%).¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.32-8.18 (m, 2H), 7.91 (dd,J=7.7, 0.8 Hz, 1H), 7.12 (s, 1H), 5.01 (dd, J=12.2, 5.3 Hz, 1H), 4.63(t, J=6.3 Hz, 1H), 3.50-3.38 (m, 2H), 3.17-3.04 (m, 2H), 2.96-2.72 (m,3H), 2.25-2.09 (m, 1H), 1.69-1.54 (m, 2H), 1.51-1.32 (m, 6H), 1.42 (s,9H). MS (ESI) [M+H]⁺: 501.3.

Example 17: tert-butyl(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxamido)octyl)carbamate (18-1)

To a solution of2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylic acid (4-1,20 mg, 0.0662 mmol, 1 equiv) in DMF (662 μL, 0.1 M) was addedN-boc-1,8-octanediamine (16.2 mg, 0.0662 mmol, 1 equiv), HATU (25.2 mg,0.0662 mmol, 1 equiv) and DIPEA (23 μL, 0.132 mmol, 2 equiv). Thereaction mixture was stirred at room temperature overnight and thenEtOAc (20 mL) was added. The organic layer was washed with satd.NaHCO₃(aq) (20 mL), water (20 mL) and brine (3×15 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (eluting with 0 to 10% MeOH inCH₂Cl₂) to give the title compound 18-1 as a white solid (19 mg, 54%).¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.23 (dd, J=7.8, 1.5 Hz, 1H),8.19-8.17 (m, 1H), 7.92 (dd, J=7.7, 0.6 Hz, 1H), 6.71 (t, J=5.6 Hz, 1H),5.00 (dd, J=12.3, 5.3 Hz, 1H), 4.55 (s, 1H), 3.55-3.38 (m, 2H),3.15-3.02 (m, 2H), 2.98-2.69 (m, 3H), 2.26-2.15 (m, 1H), 1.68-1.56 (m,2H), 1.43 (s, 9H), 1.39-1.23 (m, 10H). MS (ESI) [M+H]⁺: 529.4.

Example 18:(Z)—N-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)butyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(I-1)

To a solution ofN-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide(19a, 8 mg, 0.02 mmol, 1 equiv) in DMF (200 μL, 0.1 M) in a 4 mL vialwas added Sunitinib acid (19b, 6.0 mg, 0.02 mmol, 1 equiv), HATU (7.6mg, 0.02 mmol, 1 equiv) and DIPEA (10.4 μL, 0.06 mmol, 2 equiv). Thereaction mixture was stirred at room temperature overnight, whereupon itwas diluted with MeOH to 4 mL and filtered. The filtrate was purified bypreparative HPLC to give the title compound I-1 as an orange solid (5mg, 36%).

¹H NMR (500 MHz, DMSO-d₆) δ 13.67 (s, 1H), 11.11 (s, 1H), 10.88 (s, 1H),8.00 (t, J=5.7 Hz, 1H), 7.81 (dd, J=8.5, 7.3 Hz, 1H), 7.75 (dd, J=9.4,2.6 Hz, 1H), 7.70 (s, 1H), 7.63 (t, J=5.7 Hz, 1H), 7.49 (d, J=7.2 Hz,1H), 7.40 (d, J=8.5 Hz, 1H), 6.95-6.89 (m, 1H), 6.84 (dd, J=8.5, 4.5 Hz,1H), 5.12 (dd, J=12.7, 5.4 Hz, 1H), 4.78 (s, 2H), 3.27-3.14 (m, 4H),2.89 (ddd, J=16.5, 13.6, 5.3 Hz, 1H), 2.67-2.52 (m, 2H), 2.41 (s, 3H),2.39 (s, 3H), 2.10-1.98 (m, 1H), 1.61-1.42 (m, 4H). MS (ESI) [M+H]⁺:685.5.

Example 19:(Z)—N-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(I-2)

To a solution ofN-(8-aminooctyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide(20a, 9.2 mg, 0.02 mmol, 1 equiv) in DMF (200 μL, 0.1 M) in a 4 mL vialwas added Sunitinib acid (19b, 6.0 mg, 0.02 mmol, 1 equiv), HATU (7.6mg, 0.02 mmol, 1 equiv) and DIPEA (10.4 μL, 0.06 mmol, 2 equiv). Thereaction mixture was stirred at room temperature overnight and thendiluted with MeOH to 4 mL and filtered. The filtrate was purified bypreparative HPLC to give the title compound I-2 as an orange solid (6mg, 41%). ¹H NMR (500 MHz, DMSO-d₆) δ 13.66 (s, 1H), 11.11 (s, 1H),10.88 (s, 1H), 7.97-7.89 (m, 1H), 7.81 (dd, J=8.6, 7.2 Hz, 1H), 7.75(dd, J=9.4, 2.6 Hz, 1H), 7.70 (s, 1H), 7.64-7.58 (m, 1H), 7.49 (d, J=7.2Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 6.96-6.89 (m, 1H), 6.84 (dd, J=8.4, 4.6Hz, 1H), 5.12 (dd, J=12.8, 5.4 Hz, 1H), 4.77 (s, 2H), 3.28-3.05 (m, 4H),2.90 (ddd, J=16.8, 13.8, 5.4 Hz, 1H), 2.65-2.52 (m, 2H), 2.42 (s, 3H),2.40 (s, 3H), 2.09-1.99 (m, 1H), 1.55-1.39 (m, 4H), 1.35-1.22 (m, 8H).MS (ESI) [M+H]⁺: 741.6.

Example 20:(Z)—N-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-7,10,13-trioxa-3-azahexadecan-16-yl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-3)

To a solution ofN-(3-(2-(2-(3-aminopropoxy)-ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide(21a, 10.7 mg, 0.02 mmol, 1 equiv) in DMF (200 μL, 0.1 M) in a 4 mL vialwas added Sunitinib acid (19b, 6.0 mg, 0.02 mmol, 1 equiv), HATU (7.6mg, 0.02 mmol, 1 equiv) and DIPEA (10.4 μL, 0.06 mmol, 2 equiv). Thereaction mixture was stirred at room temperature overnight and thendiluted with MeOH to 4 mL and filtered. The filtrate was purified bypreparative HPLC to give the title compound I-3 as an orange solid (7mg, 43%). ¹H NMR (500 MHz, DMSO-d₆) δ 13.67 (s, 1H), 11.11 (s, 1H),10.87 (s, 1H), 7.94 (t, J=5.8 Hz, 1H), 7.80 (dd, J=8.5, 7.2 Hz, 1H),7.75 (dd, J=9.4, 2.6 Hz, 1H), 7.70 (s, 1H), 7.59 (t, J=5.6 Hz, 1H), 7.48(d, J=7.3 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 6.96-6.88 (m, 1H), 6.84 (dd,J=8.4, 4.5 Hz, 1H), 5.11 (dd, J=12.8, 5.5 Hz, 1H), 4.76 (s, 2H),3.55-3.43 (m, 10H), 3.40 (t, J=6.3 Hz, 2H), 3.27 (q, J=6.6 Hz, 2H), 3.20(q, J=6.6 Hz, 2H), 2.89 (ddd, J=16.9, 13.8, 5.4 Hz, 1H), 2.68-2.51 (m,2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.09-1.98 (m, 1H), 1.79-1.69 (m, 2H),1.66 (t, J=6.6 Hz, 2H). MS (ESI) [M+H]⁺: 817.8.

Example 21:(Z)—N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-4)

To a 4 mL vial containing tert-butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)carbamate(5-1, 22.1 mg, 0.05 mmol, 1 equiv) was added 4M HCl in dioxane (300 μL),and the reaction mixture was stirred at room temperature for 1 h. Uponreaction completion (monitored by LCMS), the volatiles were removed invacuo, and the residue was taken up in DMF (500 μL, 0.1 M). Sunitinibacid (19b, 14.9 mg, 0.05 mmol, 1 equiv), HATU (18.9 mg, 0.05 mmol, 1equiv) and DIPEA (43.3 μL, 0.249 mmol, 4 equiv) were added and thereaction mixture was stirred at room temperature overnight and thendiluted with MeOH to 4 mL and filtered. The filtrate was purified bypreparative HPLC to give the title compound I-4 as an orange solid (4.3mg, 14%). ¹H NMR (500 MHz, Methanol-d₄) δ 7.64 (d, J=8.4 Hz, 1H), 7.56(s, 1H), 7.47-7.33 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.01-6.80 (m, 3H),5.07 (dd, J=12.3, 5.5 Hz, 1H), 3.56-3.48 (m, 2H), 3.39-3.31 (m, 2H),2.97-2.75 (m, 3H), 2.55 (s, 3H), 2.49 (s, 3H), 2.19 (dd, J=7.7, 2.9 Hz,1H), 1.96-1.77 (m, 4H). MS (ESI) [M+H]⁺: 627.3.

Example 22:(Z)—N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-5)

To a 4 mL vial containing tert-butyl(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)-carbamate(6-1, 14.9 mg, 0.0325 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (325 μL, 0.1 M). Sunitinibacid (19b, 9.8 mg, 0.0325 mmol, 1 equiv), HATU (12.4 mg, 0.0325 mmol, 1equiv) and DIPEA (28.3 μL, 0.162 mmol, 4 equiv) were then added. Thereaction mixture was stirred at room temperature overnight and thendiluted with MeOH to 4 mL and filtered. The filtrate was purified bypreparative HPLC to give the title compound I-5 as an orange solid (3.3mg, 16%). ¹H NMR (500 MHz, Methanol-d₄) δ 7.63-7.53 (m, 2H), 7.40 (dt,J=8.9, 1.5 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 6.95-6.82 (m, 3H), 5.05 (dd,J=12.5, 5.5 Hz, 1H), 3.44 (t, J=6.9 Hz, 2H), 3.30 (t, J=6.9 Hz, 2H),2.91-2.68 (m, 3H), 2.51 (s, 3H), 2.46 (s, 3H), 2.19-2.07 (m, 1H),1.83-1.68 (m, 4H), 1.64-1.53 (m, 2H). MS (ESI) [M+H]⁺: 641.4.

Example 23:(Z)—N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(I-6)

To a 4 mL vial containing tert-butyl(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)carbamate(7-1, 19.1 mg, 0.0404 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the resulting mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (202 μL, 0.2 M). Sunitinibacid (19b, 12.1 mg, 0.0404 mmol, 1 equiv), HATU (15.4 mg, 0.0250 mmol, 1equiv) and DIPEA (21.1 μL, 0.121 mmol, 4 equiv) were added. The reactionmixture was stirred at room temperature overnight and then diluted withMeOH to 4 mL and filtered. The filtrate was purified by preparative HPLCto give the title compound I-6 as an orange solid (3.3 mg, 13%). ¹H NMR(500 MHz, Methanol-d4) δ 7.61 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.42-7.37(m, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.96-6.85 (m, 3H), 5.06 (dd, J=12.3,5.4 Hz, 1H), 3.46 (t, J=7.0 Hz, 2H), 3.29 (t, J=7.0 Hz, 2H), 2.98-2.72(m, 3H), 2.54 (s, 3H), 2.50 (s, 3H), 2.16 (ddd, J=10.5, 5.3, 2.8 Hz,1H), 1.83-1.69 (m, 4H), 1.65-1.51 (m, 4H). MS (ESI) [M+H]⁺: 655.4.

Example 24:(Z)—N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-7)

To a 4 mL vial containing tert-butyl(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamate(8-1, 12.5 mg, 0.025 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion of as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (161 μL, 0.1 M). Sunitinibacid (19b, 7.5 mg, 0.025 mmol, 1 equiv), HATU (9.5 mg, 0.025 mmol, 1equiv) and DIPEA (17.4 μL, 0.0999 mmol, 4 equiv) were added, and thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo, and the residue was purified by flashcolumn chromatography on silica gel (eluting with 0 to 10% MeOH inCH₂Cl₂) to give the title compound I-7 as an orange solid (8 mg, 47%).¹H NMR (500 MHz, DMSO-d₆) δ 13.67 (s, 1H), 11.05 (s, 1H), 10.88 (s, 1H),7.76 (dd, J=9.5, 2.6 Hz, 1H), 7.71 (s, 1H), 7.62 (t, J=5.7 Hz, 1H), 7.56(d, J=8.4 Hz, 1H), 7.11 (t, J=5.3 Hz, 1H), 6.97-6.90 (m, 2H), 6.85 (ddt,J=8.4, 2.9, 1.3 Hz, 2H), 5.03 (dd, J=12.7, 5.4 Hz, 1H), 3.71-3.53 (m,2H), 3.26-3.10 (m, 4H), 2.88 (ddd, J=16.6, 13.7, 5.3 Hz, 1H), 2.63-2.52(m, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.00 (ddd, J=10.7, 5.8, 3.4 Hz,1H), 1.63-1.46 (m, 4H), 1.44-1.31 (m, 6H). MS (ESI) [M+H]⁺: 683.6.

Example 25:(Z)—N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-8)

To a 4 mL vial containing 4 mL vial, tert-butyl(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)carbamate(9-1, 16.2 mg, 0.0352 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (352 μL, 0.1 M). Sunitinibacid (19b, 10.6 mg, 0.0352 mmol, 1 equiv), HATU (13.4 mg, 0.0352 mmol, 1equiv) and DIPEA (24.3 μL, 0.141 mmol, 4 equiv) were added. The reactionmixture was stirred at room temperature overnight and then diluted withMeOH to 4 mL and filtered. The filtrate was purified by preparative HPLCto give the title compound I-8 as an orange solid (3.1 mg, 14%). ¹H NMR(500 MHz, Methanol-d₄) δ 7.51-7.43 (m, 2H), 7.36 (dd, J=9.2, 2.6 Hz,1H), 6.95 (d, J=2.2 Hz, 1H), 6.83-6.78 (m, 3H), 4.93 (dd, J=12.4, 5.5Hz, 1H), 3.69 (t, J=5.2 Hz, 2H), 3.64 (t, J=5.3 Hz, 2H), 3.55-3.50 (m,2H), 3.39 (t, J=5.2 Hz, 2H), 2.79-2.70 (m, 1H), 2.68-2.56 (m, 2H), 2.39(s, 3H), 2.33 (s, 3H), 2.04-1.95 (m, 1H). MS (ESI) [M+H]⁺: 643.4.

Example 26:(Z)—N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)-ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl-1H-pyrrole-3-carboxamide(1-9)

To a 4 mL vial containing tert-butyl(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl)carbamate(10-1, 10.5 mg, 0.0208 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (208 μL, 0.1 M). Sunitinibacid (19b, 6.3 mg, 0.0208 mmol, 1 equiv), HATU (7.9 mg, 0.0208 mmol, 1equiv) and DIPEA (14.5 μL, 0.0832 mmol, 4 equiv) were added. Theresulting mixture was stirred at room temperature overnight and thendiluted with MeOH to 4 mL and filtered. The filtrate was purified bypreparative HPLC to give the title compound I-9 as an orange solid (4.0mg, 30%). ¹H NMR (500 MHz, Methanol-d₄) δ 7.52 (d, J=8.3 Hz, 1H), 7.47(s, 1H), 7.34 (dt, J=8.9, 1.6 Hz, 1H), 6.99 (d, J=2.1 Hz, 1H), 6.95-6.90(m, 2H), 6.83 (dd, J=8.4, 2.2 Hz, 1H), 5.03 (dd, J=12.5, 5.5 Hz, 1H),3.80 (td, J=5.2, 2.6 Hz, 10H), 3.68 (t, J=5.2 Hz, 2H), 2.92-2.74 (m,3H), 2.58 (s, 3H), 2.52 (s, 3H), 2.22-2.12 (m, 1H). MS (ESI) [M+H]⁺:687.4.

Example 27:(Z)-2-(2,6-dioxopiperidin-3-yl)-N-(8-(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)octyl)-1,3-dioxoisoindoline-5-carboxamide(I-10)

To a 4 mL vial containing tert-butyl(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxamido)octyl)carbamate(18-1, 18.8 mg, 0.0356 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (356 μL, 0.1 M). Sunitinibacid (19b, 10.7 mg, 0.0356 mmol, 1 equiv), HATU (13.5 mg, 0.0356 mmol, 1equiv) and DIPEA (18.6 μL, 0.107 mmol, 4 equiv) were added, and theresulting mixture was stirred at room temperature overnight. Thereaction mixture was then concentrated in vacuo, and the crude residuewas purified by flash column chromatography on silica gel (luting with 0to 10% MeOH in CH₂Cl₂) to give the title compound I-10 as an orangesolid (10.8 mg, 43%). ¹H NMR (500 MHz, DMSO-d₆) δ 13.65 (s, 1H), 11.14(s, 1H), 10.87 (s, 1H), 8.85 (t, J=5.5 Hz, 1H), 8.41-8.26 (m, 2H), 8.02(d, J=7.7 Hz, 1H), 7.75 (dd, J=9.4, 2.6 Hz, 1H), 7.70 (s, 1H), 7.62 (t,J=5.7 Hz, 1H), 6.92 (ddd, J=9.6, 8.4, 2.6 Hz, 1H), 6.84 (dd, J=8.5, 4.6Hz, 1H), 5.19 (dd, J=12.9, 5.5 Hz, 1H), 3.32-3.25 (m, 2H), 3.20 (q,J=6.6 Hz, 2H), 2.95-2.84 (m, 1H), 2.67-2.57 (m, 2H), 2.41 (s, 3H), 2.39(s, 3H), 2.15-2.03 (m, 1H), 1.53 (dd, J=27.7, 6.7 Hz, 4H), 1.40-1.29 (m,8H). MS (ESI) [M+H]⁺: 711.4.

Example 28:(Z)-2-(2,6-dioxopiperidin-3-yl)-N-(6-(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)hexyl)-1,3-dioxoisoindoline-5-carboxamide(I-11)

To a 4 mL vial containing tert-butyl(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxamido)hexyl)carbamate(17-1, 19.0 mg, 0.038 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (380 μL, 0.1 M). Sunitinibacid (19b, 11.4 mg, 0.0380 mmol, 1 equiv), HATU (14.4 mg, 0.0380 mmol, 1equiv) and DIPEA (19.8 μL, 0.114 mmol, 4 equiv) were added, and theresulting mixture was stirred at room temperature overnight. Thereaction mixture was concentrated in vacuo, and the crude residue waspurified by flash column chromatography on silica gel (eluting with 0 to10% MeOH in CH₂Cl₂) to give the title compound I-11 as an orange solid(7.3 mg, 29%). ¹H NMR (500 MHz, DMSO-d₆) δ 13.66 (s, 1H), 11.14 (s, 1H),10.88 (s, 1H), 8.86 (t, J=5.5 Hz, 1H), 8.35 (d, J=1.2 Hz, 1H), 8.33 (dd,J=7.8, 1.5 Hz, 1H), 8.05-8.00 (m, 1H), 7.75 (dd, J=9.5, 2.7 Hz, 1H),7.70 (s, 1H), 7.63 (t, J=5.7 Hz, 1H), 6.92 (ddd, J=9.6, 8.5, 2.6 Hz,1H), 6.84 (dd, J=8.5, 4.6 Hz, 1H), 5.19 (dd, J=12.9, 5.5 Hz, 1H), 3.22(q, J=6.5 Hz, 2H), 3.14 (qd, J=7.3, 4.3 Hz, 2H), 2.96-2.84 (m, 1H),2.68-2.57 (m, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.14-2.03 (m, 1H),1.66-1.47 (m, 4H), 1.43-1.32 (m, 4H). MS (ESI) [M+H]⁺: 684.4.

Example 29:(Z)—N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-12)

To a 4 mL vial containingtert-butyl(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate(16-1, 10.0 mg, 0.0 mmol, 1 equiv) was added 4M HCl in dioxane (300 μL),and the reaction mixture was stirred at room temperature for 1 h. Uponcompletion as monitored by LCMS, the volatiles were removed in vacuo,and the residue was taken up in DMF (200 μL, 0.1 M). Sunitinib acid(19b, 6.0 mg, 0.02 mmol, 1 equiv), HATU (7.6 mg, 0.02 mmol, 1 equiv) andDIPEA (10.4 μL, 0.06 mmol, 3 equiv) were added, and the resultingmixture was stirred at room temperature overnight. The reaction mixturewas concentrated in vacuo, and the residue was purified by flash columnchromatography on silica gel (eluting with 0 to 10% MeOH in CH₂Cl₂) togive the title compound I-12 as an orange solid (9 mg, 66%). ¹H NMR (500MHz, DMSO-d₆) δ 13.66 (s, 1H), 11.09 (s, 1H), 10.88 (s, 1H), 7.76 (dd,J=9.4, 2.6 Hz, 1H), 7.71 (s, 1H), 7.65-7.56 (m, 2H), 7.10 (d, J=8.6 Hz,1H), 7.02 (d, J=7.0 Hz, 1H), 6.93 (ddd, J=9.6, 8.4, 2.6 Hz, 1H), 6.85(ddd, J=7.8, 5.0, 2.7 Hz, 1H), 6.54 (t, J=5.9 Hz, 1H), 5.05 (dd, J=12.7,5.5 Hz, 1H), 3.31-3.26 (m, 2H), 3.25-3.18 (m, 2H), 2.95-2.82 (m, 1H),2.66-2.53 (m, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.08-1.97 (m, 1H), 1.59(t, J=7.0 Hz, 4H), 1.55-1.46 (m, 4H), 1.41-1.31 (m, 4H). MS (ESI)[M+H]⁺: 683.3.

Example 30:Z)—N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-13)

To a 4 mL vial containing tert-butyl(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamate(15-1, 36.0 mg, 0.0762 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (381 μL, 0.2 M). Sunitinibacid (19b, 22.9 mg, 0.0762 mmol, 1 equiv), HATU (29.0 mg, 0.0762 mmol, 1equiv) and DIPEA (39.8 μL, 0.229 mmol, 3 equiv) were added, and thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo, and the crude residue was purified byflash column chromatography on silica gel (eluting with 0 to 10% MeOH inCH₂Cl₂) to give the title compound as 1-13 an orange solid (9.9 mg,20%). ¹H NMR (500 MHz, DMSO-d₆) δ 13.66 (s, 1H), 11.09 (s, 1H), 10.88(s, 1H), 7.75 (dd, J=9.4, 2.6 Hz, 1H), 7.70 (s, 1H), 7.64-7.56 (m, 2H),7.10 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.92 (ddd, J=9.6, 8.5,2.6 Hz, 1H), 6.84 (dd, J=8.5, 4.5 Hz, 1H), 6.55 (t, J=5.9 Hz, 1H), 5.05(dd, J=12.7, 5.4 Hz, 1H), 3.22 (q, J=6.6 Hz, 2H), 3.18-3.10 (m, 2H),2.93-2.83 (m, 1H), 2.68-2.53 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H),2.08-1.99 (m, 1H), 1.56 (dt, J=37.0, 6.9 Hz, 4H), 1.46-1.33 (m, 4H). MS(ESI) [M+H]⁺: 655.4.

Example 31:(Z)—N-(8-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzamido)octyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-14)

To a 4 mL vial containingtert-butyl(8-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzamido)octyl)carbamate(14-1, 15 mg, 0.0237 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (237 μL, 0.1 M). Sunitinibacid (19b, 7.1 mg, 0.0237 mmol, 1 equiv), HATU (9.0 mg, 0.0237 mmol, 1equiv) and DIPEA (16.5 μL, 0.0947 mmol, 4 equiv) were added, and thereaction mixture was stirred at room temperature overnight. Theresulting mixture was concentrated in vacuo, and the crude residue waspurified by flash column chromatography on silica gel (eluting with 0 to10% MeOH in CH₂Cl₂) to give the title compound I-14 as an orange solid(5.1 mg, 26%). MS (ESI) [M+H]⁺: 816.5.

Example 32:(Z)—N-(8-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)benz-amido)octyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(1-15)

To a 4 mL vial containingtert-butyl(8-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)benzamido)octyl)carbamate(12-1, 13 mg, 0.0205 mmol, 1 equiv) was added 4M HCl in dioxane (300μL), and the reaction mixture was stirred at room temperature for 1 h.Upon completion as monitored by LCMS, the volatiles were removed invacuo, and the residue was taken up in DMF (205 μL, 0.1 M). Sunitinibacid (19b, 6.2 mg, 0.0205 mmol, 1 equiv), HATU (7.8 mg, 0.0205 mmol, 1equiv) and DIPEA (14.3 μL, 0.0205 mmol, 4 equiv) were added, and thereaction mixture was stirred at room temperature overnight. Theresulting mixture was concentrated in vacuo, and the crude residue waspurified by flash column chromatography on silica gel (0-10% MeOH inCH₂Cl₂) to give the title compound I-15 as an orange solid (4 mg, 26%).MS (ESI) [M+H]⁺: 816.6.

Example 33: Cell Viability Assay

Dose-ranging viability assays were performed using cellular ATP contentas a proxy for cellular viability (ATPlite assay, Promega®).Bifunctional compounds of the application were incubated for 72 hourswith DNA41, HBP-ALL, HSB2, JURKAT, KOPTK1, MOLT4, MOLT4-CRBN^(−/−),MOLT16, CCRF-CEM, P12-ICHIKAWA, PF382, RPMI-8402, SKW3, and SUPT11cells. All experiments were conducted in quadruplicates. The resultingdata were then converted to represent a single value per replicate (areaunder the curve, AUC) and shown as a heatmap. (FIG. 1). The percentageviability (relative to controls) in the various cell lines treated withSunitinib, Compound I-2, Compound I-6, Compound I-7, Compound I-10,Compound I-11, Compound I-13, or Compound I-37 is shown in FIGS. 1 and2A-2N.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the present application.

All patents, patent applications, and literature references cited hereinare hereby expressly incorporated by reference.

1. A bifunctional compound of Formula X:

wherein: the Targeting Ligand (TL) is capable of binding to one or moreprotein kinases; the Linker is a group that covalently binds to theTargeting Ligand and the Degron; and the Degron is capable of binding toa ubiquitin ligase.
 2. The bifunctional compound of claim 1, wherein theTargeting Ligand is of Formula TL-I, TL-II, TL-III, TL-IV, TL-V, orTL-VI:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein: X₁ is NR₅ or O; each R₁ and each R₄are independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkoxy, halogen, OH, or NH₂; R₂ and R₃ are eachindependently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; R₅ is H, (C₁-C₄)alkyl, (C₁-C₄) haloalkyl, or C(O)(C₁-C₄) alkyl; n1 is 0, 1, 2 or 3; andn2 is 0, 1, or 2; or

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein: A is (C₆-C₁₀) aryl or 5- or 6-memberedheteroaryl comprising 1-3 heteroatoms selected from N, S, and O, whereinthe aryl or heteroaryl are optionally substituted with one to three R₉;X₂ is O, S, or NR₁₀; X₃ is N or CR₁₁; each R₆ is independently (C₁-C₄)alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen,OH, NH₂, (C₁-C₄) alkylamino, (C₁-C₄) dialkylamino, NHS(O)₂(C₁-C₄) alkyl,or N((C₁-C₄) alkyl)S(O)₂(C₁-C₄) alkyl; R₇ is H, (C₁-C₄) alkyl, or(C₁-C₄) haloalkyl; each R₈ and each R₉ are independently (C₁-C₄) alkyl,(C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, orNH₂; R₁₀ is H or (C₁-C₄) alkyl; R₁₁ is (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; q1 is 0, 1, 2,3, or 4; and q2 is 0, 1, or 2; or

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein: B₁ is (C₆-C₁₀) aryl or 5- or6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, andO, wherein the aryl or heteroaryl are optionally substituted with one tothree R₁₅; B₂ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising1-3 heteroatoms selected from N, S, and O, wherein the aryl orheteroaryl are optionally substituted with one to three R₁₆; R₁₂ is H or(C₁-C₄) alkyl; each R₁₃ is independently (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; R₁₄is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; each R₁₅ and each R₁₆ areindependently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, halogen, OH, or NH₂; and r1 is 0, 1, 2, 3 or 4; or

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein: B₃ is (C₆-C₁₀) aryl or 5- or6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, andO, wherein the aryl or heteroaryl are optionally substituted with one tothree R₁₉; B₄ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising1-3 heteroatoms selected from N, S, and O, wherein the aryl orheteroaryl are optionally substituted with one to three R₂₀; R₁₇ is H or(C₁-C₄) alkyl; R₁₈ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; or each R₁₉ and eachR₂₀ are independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkoxy, halogen, OH, or NH₂ or

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein: B₅ is (C₆-C₁₀) aryl or 5- or6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, andO, wherein the aryl or heteroaryl are optionally substituted with one tothree R₂₆; Y₁ is C(O)NR₂₅ or NR₂₅C(O); R₂₁ is H, (C₁-C₄) alkyl, or(C₁-C₄) haloalkyl; R₂₂ and R₂₃ are each independently H, (C₁-C₄) alkyl,(C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, orNH₂; each R₂₄ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, or C(O)(C₁-C₄) alkyl; R₂₅ is H,(C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; each R₂₆ is independently (C₁-C₄)alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen,OH, or NH₂; and s2 is 0, 1, 2, or 3; or

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein: B₆ is (C₆-C₁₀) aryl or 5- or6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, andO, wherein the aryl or heteroaryl are optionally substituted with one tothree R₃₁; B₇ is (C₆-C₁₀) aryl or 5- or 6-membered heteroaryl comprising1-3 heteroatoms selected from N, S, and O, wherein the aryl orheteroaryl are optionally substituted with one to three R₃₂; X₄ is O orNR₃₃; R₂₇ and R₂₈ are each independently H, (C₁-C₄) alkyl, or (C₁-C₄)haloalkyl; each R₂₉ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; each R₃₀ isindependently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, halogen, or C(O)(C₁-C₄) alkyl; each R₃₁ and each R₃₂ areindependently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, halogen, OH, or NH₂; R₃₃ is H, (C₁-C₄) alkyl, or (C₁-C₄)haloalkyl; s3 and s4 are each independently 0, 1, 2, or 3; and s5 is 1or 2; wherein the Targeting Ligand is bonded to the Linker via the

next to

in TL-I,

in TL-II,

in TL-III,

in TL-IV,

in TL-V, and

in TL-VI.
 3. The bifunctional compound of claim 2, wherein the TargetingLigand is of Formula TL-I. 4.-11. (canceled)
 12. The bifunctionalcompound of claim 2, wherein the Targeting Ligand is of Formula TL-II.13.-19. (canceled)
 20. The bifunctional compound of claim 2, wherein theTargeting Ligand is of Formula TL-III. 21.-28. (canceled)
 29. Thebifunctional compound of claim 2, wherein the Targeting Ligand is ofFormula TL-IV. 30.-34. (canceled)
 35. The bifunctional compound of claim2, wherein the Targeting Ligand is of Formula TL-V. 36.-41. (canceled)42. The bifunctional compound of claim 2, wherein the Targeting Ligandis of Formula TL-VI. 43.-49. (canceled)
 50. The bifunctional compound ofclaim 2, wherein the Targeting Ligand is of Formula TL-Ia, TL-IIa,TL-IIIa, TL-IVa, TL-Va, or TL-VIa:


51. The bifunctional compound of claim 1, wherein the Linker is ofFormula L1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein p1 isan integer selected from 0 to 12; p2 is an integer selected from 0 to12; p3 is an integer selected from 1 to 6; each W is independentlyabsent, CH₂, O, S, or NR₃₄; Z₁ is absent, C(O), CH₂, O, (CH₂)_(j)NR₃₄,O(CH₂)_(j)C(O)NR₃₄, C(O)NR₃₄, (CH₂)_(j)C(O)NR₃₄, NR₃₄C(O),(CH₂)_(j)NR₃₄C(O), C(O)NR₃₄(CH₂)_(j)C(O)NR₃₄, C(O)(CH₂)_(j)C(O)NR₃₄,(CH₂)_(k)NR₃₄(CH₂)_(j)C(O)NR₃₄, or NR₃₄(CH₂)_(j)C(O)NR₃₄; each R₃₄ isindependently H or C₁-C₃ alkyl; j is 1, 2, or 3; k is 1, 2, or 3; and Q₁is absent, C(O), NHC(O)(CH₂)₀₋₁, OCH₂C(O), O(CH₂)₁₋₂, or

wherein the Linker is covalently bonded to a Degron via the

next to Q₁, and covalently bonded to a Targeting Ligand (TL) via the

next to Z₁.
 52. The bifunctional compound of claim 51, wherein theLinker is selected from:


53. The bifunctional compound of claim 1, wherein the Degron is ofFormula D1 or D2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein: Y is abond, (CH₂)₁₋₆, (CH₂)₀₋₆—O, (CH₂)₀₋₆—C(O)NR₃₅, (CH₂)₀₋₆—NR₃₅C(O),(CH₂)₀₋₆—NH, or (CH₂)₀₋₆—NR₃₆; Z₃ is C(O) or C(R₃₇)₂; R₃₅ is H or C₁-C₆alkyl; R₃₆ is C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl; each R₃₇ is independentlyH or C₁-C₃ alkyl; each R₃₈ is independently C₁-C₃ alkyl; R₃₉ is H,deuterium, C₁-C₃ alkyl, F, or C₁; each R₄₀ is independently halogen, OH,C₁-C₆ alkyl, or C₁-C₆ alkoxy; q is 0, 1, or 2; and v is 0, 1, 2, or 3,and each R₄₁ is independently C₁-C₃ alkyl; q′ is 0, 1, 2, 3 or 4; andR₄₂ is H or C₁-C₃ alkyl, wherein the Degron is covalently bonded to theLinker via

54.-55. (canceled)
 56. The bifunctional compound of claim 53, whereinthe Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i,D1j, D1k, D1l, D2a, D2b, D2c, or D2d:

57.-59. (canceled)
 60. A pharmaceutical composition comprising atherapeutically effective amount of the bifunctional compound of claim1, or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 61.A method of inhibiting or modulating the amount of at least one proteinkinase, comprising administering to a subject in need thereof aneffective amount of a compound of claim
 1. 62. (canceled)
 63. A methodof treating or preventing a disease in which at least one protein kinaseplays a role, comprising administering to a subject in need thereof aneffective amount of a compound of claim
 1. 64.-66. (canceled)
 67. Amethod of inhibiting or modulating the amount of a protein kinase,comprising administering to a subject in need thereof an effectiveamount of a compound of claim
 1. 68.-75. (canceled)